Cyclic derivatives as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I):  
                 
or pharmaceutically acceptable salt forms thereof, useful for the prevention of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma, processes for preparing and intermediates thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefits of U.S. ProvisionalApplication No. 60/446,850, filed Feb. 12, 2003, which is expresslyincorporated fully herein by reference.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases, allergic and autoimmune diseases, and in particular, asthma,rheumatoid arthritis, atherosclerosis, and multiple sclerosis, processesof forming and intermediates thereof.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in: Luster, New Eng. J. Bed. 1998,338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two majorclasses of chemokines, CXC and CC, depending on whether the first twocysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CX₃C chemokine) that do not fall into either of the majorchemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns (reviewed in Zlotnik and OshieImmunity 2000, 12, 121): CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α,MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72, 415-425, andLuster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A and CCR-2B (or“CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3,MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994, 91,2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3 (or“CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster,New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-41”)[TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495-19500, andLuster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or “CKR-5” OR“CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al., Biochemistry 1996,35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba, et al.,J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or “CKR-7” or “CC-CKR-7”)[ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or“CKR-8” or “CC-CKR-8”) [I-309] (Napolitano et al., J. Immunol., 1996,157, 2759-2763); CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3](Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11[MCP-1, MCP-2, and MCP-4] (Schweickert, et al., J. Biol. Chem. 2000,275, 90550).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

The chemokines and their cognate receptors have been implicated as beingimportant mediators of inflammatory, infectious, and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (reviewed in: P. H. Carter, Current Opinion in ChemicalBiology 2002, 6, 510; Trivedi, et al, Ann. Reports Med. Chem. 2000, 35,191; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Premack andSchall, Nature Medicine 1996, 2, 1174). For example, the chemokinemonocyte chemoattractant-1 (MCP-1) and its receptor CC ChemokineReceptor 2 (CCR-2) play a pivotal role in attracting leukocytes to sitesof inflammation and in subsequently activating these cells. When thechemokine MCP-1 binds to CCR-2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. Demonstration of the importance of the MCP-1/CCR-2interaction has been provided by experiments with genetically modifiedmice. MCP-1 −/− mice had normal numbers of leukocytes and macrophages,but were unable to recruit monocytes into sites of inflammation afterseveral different types of immune challenge (Bao Lu, et al., J. Exp.Med. 1998, 187, 601). Likewise, CCR-2−/− mice were unable to recruitmonocytes or produce interferon-γ when challenged with various exogenousagents; moreover, the leukocytes of CCR-2 null mice did not migrate inresponse to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100,2552), thereby demonstrating the specificity of the MCP-1/CCR-2interaction. Two other groups have independently reported equivalentresults with different strains of CCR-2−/− mice (William A. Kuziel, etal., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, etal., J. Exp. Med. 1997, 186, 1757). The viability and generally normalhealth of the MCP-1 −/− and CCR-2−/− animals is noteworthy, in thatdisruption of the MCP-1/CCR-2 interaction does not induce physiologicalcrisis. Taken together, these data lead one to the conclusion thatmolecules that block the actions of MCP-1 would be useful in treating anumber of inflammatory and autoimmune disorders. This hypothesis has nowbeen validated in a number of different animal disease models, asdescribed below.

It is known that MCP-1 is upregulated in patients with rheumatoidarthritis (Alisa Koch, et al., J. Clin. Invest. 1992, 90, 772-779).Moreover, several studies have demonstrated the potential therapeuticvalue of antagonism of the MCP-1/CCR2 interaction in treating rheumatoidarthritis. A DNA vaccine encoding MCP-1 was shown recently to amelioratechronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory diseasesymptoms could be controlled via direct administration of antibodies forMCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J.Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis(Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps mostsignificantly, a peptide antagonist of MCP-1, MCP-1 (9-76), was shownboth to prevent disease onset and to reduce disease symptoms (dependingon the time of administration) in the MRL-lpr mouse model of arthritis(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).

It is known that MCP-1 is upregulated in atherosclerotic lesions, and ithas been shown that circulating levels of MCP-1 are reduced throughtreatment with therapeutic agents, plays a role in disease progression(Abdolreza Rezaie-Majd, et al, Arterioscler. Thromb. Vasc. Biol. 2002,22, 1194-1199). Four key studies have demonstrated the potentialtherapeutic value of antagonism of the MCP-1/CCR2 interaction intreating atherosclerosis. For example, when MCP-1 −/− mice are matedwith LDL receptor-deficient mice, an 83% reduction in aortic lipiddeposition was observed (Long Gu, et al., Mol. Cell. 1998, 2, 275).Similarly, when MCP-1 was genetically ablated from mice which alreadyoverexpressed human apolipoprotein B, the resulting mice were protectedfrom atherosclerotic lesion formation relative to the MCP-1 +/+ apoBcontrol mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773).Likewise, when CCR-2 −/− mice are crossed with apolipoprotein E −/−mice, a significant decrease in the incidence of atherosclerotic lesionswas observed (Landin Boring, et al, Nature 1998, 394, 894). Finally,when apolipoprotein E −/− mice are administered a gene encoding apeptide antagonist of CCR2, then lesion size is decreased and plaquestability is increased (W. Ni, et al. Circulation 2001, 103, 2096-2101).

It is known that MCP-1 is upregulated in human multiple sclerosis, andit has been shown that effective therapy with interferon b-1b reducesMCP-1 expression in peripheral blood mononuclear cells, suggesting thatMCP-1 plays a role in disease progression (Carla Iarlori, et al., J.Neuroimmunol. 2002, 123, 170-179). Other studies have demonstrated thepotential therapeutic value of antagonism of the MCP-1/CCR-2 interactionin treating multiple sclerosis; all of these studies have beendemonstrated in experimental autoimmune encephalomyelitis (EAE), theconventional animal model for multiple sclerosis. Administration ofantibodies for MCP-1 to animals with EAE significantly diminisheddisease relapse (K. J. Kennedy, et al., J. Neuroimmunol. 1998, 92, 98).Furthermore, two recent reports have now shown that CCR-2 −/− mice areresistant to EAE (Brian T. Fife, et al., J. Exp. Med. 2000, 192, 899;Leonid Izikson, et al., J. Exp. Med. 2000, 192, 1075).

It is known that MCP-1 is upregulated in patients who developbronchiolitis obliterans syndrome after lung transplantation (MartineReynaud-Gaubert, et al., J. of Heart and Lung Transplant., 2002, 21,721-730; John Belperio, et al., J. Clin. Invest. 2001, 108, 547-556). Ina murine model of bronchiolitis obliterans syndrome, administration ofan antibody to MCP-1 led to attenuation of airway obliteration;likewise, CCR2 −/− mice were resistant to airway obliteration in thissame model (John Belperio, et al., J. Clin. Invest. 2001, 108, 547-556).These data suggest that antagonism of MCP-1/CCR2 may be beneficial intreating rejection of organs following transplantation.

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating asthma.Sequestration of MCP-1 with a neutralizing antibody inovalbumin-challenged mice resulted in marked decrease in bronchialhyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J.Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airwayinflammation in Schistosoma mansoni egg-challenged mice through theadministration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J.Immunol. 1997, 158, 4398). Consistent with this, MCP-1 −/− micedisplayed a reduced response to challenge with Schistosoma mansoni egg(Bao Lu, et al., J. Exp. Med. 1998, 187, 601).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating kidney disease.Administration of antibodies for MCP-1 in a murine model ofglomerularnephritis resulted in a marked decrease in glomerular crescentformation and deposition of type I collagen (Clare M. Lloyd, et al., J.Exp. Med. 1997, 185, 1371). In addition, MCP-1 −/− mice with inducednephrotoxic serum nephritis showed significantly less tubular damagethan their MCP-1 +/+counterparts (Gregory H. Tesch, et al., J. Clin.Invest. 1999, 103, 73).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating systemic lupus erythematosus.Crossing of MCP-1−/− mice with MRL-FAS^(lPr) mice—the latter of whichhave a fatal autoimmune disease that is analogous to human systemiclupus erythematosus—results mice that have less disease and longersurvival than the wildtype MRL-FAS^(lPr) mice (Gregory H. Tesch, et al.,J. Exp. Med. 1999, 190, 1813).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating colitis. CCR-2 −/− mice wereprotected from the effects of dextran sodium sulfate-induced colitis(Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating alveolitis. When rats with IgAimmune complex lung injury were treated intravenously with antibodiesraised against rat MCP-1 (JE), the symptoms of alveolitis were partiallyalleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating cancer. When immunodeficientmice bearing human breast carcinoma cells were treated with ananti-MCP-1 antibody, inhibition of lung micrometastases and increases insurvival were observed (Rosalba Salcedo, et al., Blood 2000, 96, 34-40).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating restinosis. Mice deficient inCCR2 showed reductions in the intimal area and in the intima/media ratio(relative to wildtype littermates) after injury of the femoral artery(Merce Roque, et al. Arterioscler. Thromb. Vasc. Biol. 2002, 22,554-559).

Other studies have provided evidence that MCP-1 is overexpressed invarious disease states not mentioned above. These reports providecorrelative evidence that MCP-1 antagonists could be useful therapeuticsfor such diseases. Two reports described the overexpression of MCP-1 inthe intestinal epithelial cells and bowel mucosa of patients withinflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59,804). Two reports describe the overexpression of MCP-1 rats with inducedbrain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, andJoan W. Berman, et al., J. Immunol. 1996, 156, 3017). Another study hasdemonstrated the overexpression of MCP-1 in rodent cardiac allografts,suggesting a role for MCP-1 in the pathogenesis of transplantarteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA1993, 90, 6086). The overexpression of MCP-1 has been noted in the lungendothelial cells of patients with idiopathic pulmonary fibrosis (HarryN. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371).Similarly, the overexpression of MCP-1 has been noted in the skin frompatients with psoriasis (M. Deleuran, et al., J. Dermatol. Sci. 1996,13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127).Finally, a recent report has shown that MCP-1 is overexpressed in thebrains and cerebrospinal fluid of patients with HIV-1-associateddementia (Alfredo Garzino-Demo, WO 99/46991).

It should also be noted that CCR-2 has been implicated as a co-receptorfor some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). Ithas also been determined that the use of CCR-2 as an HIV co-receptor canbe correlated with disease progression (Ruth I. Connor, et al., J. Exp.Med. 1997, 185, 621). This finding is consistent with the recent findingthat the presence of a CCR-2 mutant, CCR2-64I, is positively correlatedwith delayed onset of HIV in the human population (Michael W. Smith, etal., Science 1997, 277, 959). Although MCP-1 has not been implicated inthese processes, it may be that MCP-1 antagonists that act via bindingto CCR-2 may have beneficial therapeutic effects in delaying the diseaseprogression to AIDS in HIV-infected patients.

Recently, a number of groups have described the development of smallmolecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, et al,Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen and Combichemreported the use of cyclic amines (A) as MCP-1 (Tatsuki Shiota, et al.,WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) and MIP-1α (ChristineTarby and Wilna Moree, WO 00/69820) antagonists. These compounds aredistinguished from those of the present invention (I) by the requirementfor the central cyclic amine grouping.

Workers at Bristol-Myers Squibb have reported the use of acyclicdiamines (B) as MCP-1 antagonists (Percy Carter and Robert Cherney,WO-02/50019).

Workers at Bristol-Myers Squibb have reported the use of cyclic diamines(C) as MCP-1 antagonists (Robert Cherney, WO-02/060859).

Workers at Pfizer have reported the use of bicyclic diamines (D) asMCP-1 antagonists (Roberto Colon-Cruz, et al., WO-02/070523).

A number of other groups have also described the development of smallmolecule antagonists of the MCP-1/CCR-2 interaction. To date,indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem. Lett. 2000,10, 1803), spiropiperidines (Tara Mirzadegan, et al., J. Biol. Chem.2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl.Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and JasonKettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; AndrewJohn Barker, et al., WO 99/07678), pyrazolone derivatives (JanakKhimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substitutedbenzimidazoles (David Thomas Connor, et al., WO 98/06703),N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclicpyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, etal., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al.,Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA,1999) have all been reported as MCP-1 antagonists.

The foregoing reference compounds are readily distinguished structurallyfrom the present invention by virtue of substantial differences in theterminal functionality, the attachment functionality, or the corefunctionality. The prior art does not disclose nor suggest the uniquecombination of structural fragments that embody in the novel compoundsdescribed herein. Furthermore, the prior art does not disclose orsuggest that the compounds of the present invention would be antagonistsof MCP-1.

It should be noted that CCR-2 is also the receptor for the chemokinesMCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338,436-445). Since the new compounds of formula (I) described hereinantagonize MCP-1 by binding to the CCR-2 receptor, it may be that thesecompounds of formula (I) are also effective antagonists of the actionsof MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR-2.Accordingly, when reference is made herein to “antagonism of MCP-1,” itis to be assumed that this is equivalent to “antagonism of chemokinestimulation of CCR-2.”

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel antagonists or partialagonists/antagonists of MCP-1 receptor activity, or pharmaceuticallyacceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides novel cyclic derivatives for use intherapy.

The present invention provides the use of novel cyclic derivatives forthe manufacture of a medicament for the treatment of inflammatorydiseases.

The present invention is directed to methods of preparing the compoundsof the present invention, and intermediates thereof.

These and other features of the invention, which will become apparentduring the following detailed description, have been achieved by theinventors' discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinB, B, Z, m, n, s, carbon b, bond (a), R¹, R², R¹⁰, R¹¹, R¹², and R¹³ aredefined below, are effective modulators of chemokine activity.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION

[1] Thus, in another embodiment, the present invention provides novelcompounds of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the    cycloalkyl group is saturated or partially unsaturated; or a    heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or    partially unsaturated, the heterocycle containing a heteroatom    selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the    heterocycle optionally containing a —C(O)—; ring B being substituted    with 0-2 R⁵;-   X is selected from O or S;-   Z is selected from a bond, —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—,    —NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —C(O)NR⁸—, —OC(O)NR⁸—,    —NR⁸C(O)O—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—,    —C(O)CR¹⁵R¹⁵—, CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—,    —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—;-   wherein neither Z nor R¹³ are connected to a carbon atom labeled    (b);-   bond (a) is a single or double bond;-   alternatively, when n is equal to 2, two atoms labeled (b) may join    through a double bond;-   E is selected from —S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—,    —C(O)—NR^(e)—, —NR^(e)C(O)NR^(e)—, —SO₂—NR^(e)—, and    NR^(e)SO₂NR^(e);-   R^(e) is independently selected from H and C₁₋₃ alkyl;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(t)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4d), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(t)NR^(4a)S(O)₂R^(4b), C₁₋₆    haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and Si substituted    with 0-2 R^(4e);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),    C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted    with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-4 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(4e), and a    (CHR)_(r)-4-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);-   R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j),    —C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h),    —NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(4h), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀    carbocyclic;-   R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;-   R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;-   R⁵, at each occurrence, is independently selected from H, ═O, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)N(→O)R^(5a)R^(5a), N₃, (CRR)_(r)C(O)OH,    (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5d), (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5c);-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆-cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),    (CH₂)_(r)OC(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b),    (CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR⁵R^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(5e);-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), —CN, and (CH₂)_(r)phenyl;-   R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(5e);-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)N^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R⁶ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl substituted    with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈    alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with    0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),    —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)C₃₋₁₀ carbocyclic residue and (CR′R′)_(r)phenyl    substituted with 0-3 R^(7e);-   alternatively, two R⁷ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted    with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3    R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, C(O)OC₁₋₅ alkyl,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR⁷,    —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(6e);-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H, and    —C(O)—C₁₋₄alkyl;-   R¹⁰ is independently selected from H, and C₁₋₄alkyl substituted with    0-1 R^(10b), alternatively, two R¹⁰ form ═O;-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, —NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),    (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),    (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(11e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),    (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)R^(12a)C(O)R^(12b),    (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(12e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹³, at each occurrence, is independently selected from H, and    C₁₋₄alkyl substituted with 0-1 R^(13b), —OH, —NH₂, F, Cl, Br, I,    —OR^(13a), —N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3    R^(13b);-   R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R^(13b), at each occurrence, is independently selected from —OH,    —SH, NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H and    C₁₋₄alkyl;-   alternatively, two R¹⁴s, along with the carbon atom to which they    are attached, join to form a C₃₋₆ carbocyclic ring;-   R¹⁵, at each occurrence, is independently selected from H,    C₁₋₄alkyl, OH, NH₂, O—C₁₋₄ alkyl, NR^(15a)R^(15a),    C(O)NR^(15a)R^(15a), NR^(15a)C(O)R^(15b), NR^(15a)C(O)OR^(15d),    OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d);-   alternatively, two R¹⁵s, along with the carbon atom or atoms to    which they are attached, join to form a C₃₋₆ carbocyclic ring;-   R^(15a), at each occurrence, is independently selected from H, and    C₁₋₄ alkyl;-   R^(15b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R^(15d), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R¹⁶ is selected from C₁₋₄ alkyl;-   l is selected from 1, 2 and 3;-   n is selected from 0, 1, 2, and 3;-   m is selected from 0 and 1;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   t, at each occurrence, is independently selected from 2, 3, and 4;-   s is selected from 0 and 1.    [2] Thus, in another embodiment, the present invention provides    novel compounds of formula (I):    or a stereoisomer or a pharmaceutically acceptable salt thereof,    wherein:-   ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the    cycloalkyl group is saturated or partially unsaturated; or a    heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or    partially unsaturated, the heterocycle containing a heteroatom    selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the    heterocycle optionally containing a —C(O)—; ring B being substituted    with 0-2 R⁵;-   X is selected from O or S;-   Z is selected from a bond, —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—,    —NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —C(O)NR⁸—, —OC(O)NR⁸—,    —NR⁸C(O)O—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—,    —C(O)CR¹⁵R¹⁵—, CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—,    —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—S(O)_(p)— and —S(O)_(p)—NR⁹—;-   wherein neither Z nor R¹³ are connected to a carbon atom labeled    (b);-   bond (a) is a single or double bond;-   alternatively, when n is equal to 2, two atoms labeled (b) may join    through a double bond;-   E is selected from —S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—,    —C(O)—NR^(e)—, —NR^(e)C(O)NR^(e)—, —SO₂—NR^(e)—, and    —NR^(e)SO₂NR^(e)—;-   R^(e) is independently selected from H and C₁₋₃ alkyl;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(t)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4d), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(t)NR^(4a)S(O)₂R^(4b), C₁₋₆    haloalkyl, a (CRR)_(r)C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-2    R^(4e);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),    C₃₋₆ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted    with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-4 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(4e), and a (CHR)_(r)-410    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(4e);-   R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j),    —C(O)NR^(4h)R^(4h), OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h),    NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(4h), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀    carbocyclic;-   R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;-   R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;-   R⁵, at each occurrence, is independently selected from H, ═O, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5d), (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5c);-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),    (CH₂)_(r)OC(O)NR^(5f)R⁵, (CH₂)_(r)NR^(5f)C(O)R^(5b),    (CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)R^(5f)S(O)₂R^(5b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(5e);-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(5e);-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R⁶ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl substituted    with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈    alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with    0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),    —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, ON,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e);-   alternatively, two R⁷ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted    with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-G membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3    R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, C(O)OC₁₋₅ alkyl,    (CH₂)_(r)SC₁₋₁₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(6e);-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H, and    —C(O)—C₁₋₄alkyl;-   R¹⁰ is independently selected from H, and C₁₋₄alkyl substituted with    0-1 R^(10b);-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),    (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)R^(11a)C(O)R^(11b),    (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)OC(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(11e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₉    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),    (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),    (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)O^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(12e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹³, at each occurrence, is independently selected from H, and    C₁₋₄alkyl substituted with 0-1 R^(13b), —OH, —NH₂, F, Cl, Br, I,    —OR^(13a), —N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3    R^(13b);-   R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R^(13b), at each occurrence, is independently selected from —OH,    —SH, NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H and    C₁₋₄alkyl;-   alternatively, two R¹⁴s, along with the carbon atom to which they    are attached, join to form a C₃₋₆ carbocyclic ring;-   R¹⁵, at each occurrence, is independently selected from H,    C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(15a)R^(15a),    C(O)NR^(15a)R^(15a), NR^(15a)C(O)R^(15b), NR^(15a)C(O)OR^(15d),    OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d);-   alternatively, two R¹⁵s, along with the carbon atom or atoms to    which they are attached, join to form a C₃₋₆ carbocyclic ring;-   R^(15a), at each occurrence, is independently selected from H, and    C₁₋₄ alkyl;-   R^(15b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R^(15d), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R¹⁶ is selected from C₁₋₄ alkyl;-   l is selected from 1, 2 and 3;-   n is selected from 0, 1, 2, and 3;-   m is selected from 0 and 1;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   t, at each occurrence, is independently selected from 2, 3, and 4;-   s is selected from 0 and 1.    [3] Thus, in a another embodiment, the present invention provides    novel compounds of formula (I)    m is 0.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being optionally substituted with 0-1 R⁵; and    R¹¹ and R¹² are H.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)NR^(5a)C(O)OR^(5d),    (CRR)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    CRR(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b),    (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),    (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆    haloalkyl;-   R^(5a), at each occurrence, is independently selected from H,    methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl is    selected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl,    hexyl, C₃ alkenyl substituted with 0-1 R^(5e), wherein the alkenyl    is selected from allyl, C₃ alkynyl substituted with 0-1 R^(5e)    wherein the alkynyl is selected from propynyl, and a (CH₂)_(r)—C₃₋₄    carbocyclic residue substituted with 0-5 R^(5e), wherein the    carbocyclic residue is selected from cyclopropyl, and cyclobutyl;-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(5e), wherein the alkyl is selected from methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a    (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-2 R^(5e),    wherein the carbocyclic residue is selected from cyclopropyl, and    cyclobutyl; and-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), wherein the alkyl is selected from    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl,    C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue    substituted with 0-3 R^(5e).

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)N(O)R^(5a)R^(5a), N₃, (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b),    (CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),    (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), CRR(CRR)_(r)NR^(5a)C(O)H,    (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),    (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆    haloalkyl;-   R^(5a), at each occurrence, is independently selected from H,    methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl is    selected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl,    hexyl, C₃ alkenyl substituted with 0-1 R^(5e), wherein the alkenyl    is selected from allyl, C₃ alkynyl substituted with 0-1 R^(5e)    wherein the alkynyl is selected from propynyl, and a (CH₂)_(r)—C₃₋₄    carbocyclic residue substituted with 0-5 R^(5e), wherein the    carbocyclic residue is selected from cyclopropyl, and cyclobutyl;-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(5e), wherein the alkyl is selected from methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a    (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-2 R^(5e),    wherein the carbocyclic residue is selected from cyclopropyl, and    cyclobutyl; and-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), wherein the alkyl is selected from    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl,    C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue    substituted with 0-3 R^(5e).

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b),    (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b);-   R, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(6e);-   R⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,    (CH₂)_(r)OH, (CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a),    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C(O)R^(5b),    (CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b),    (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,    cyclopropyl, and cyclobutyl; and-   r, at each occurrence, is selected from 0, 1, and 2.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹ is selected from phenyl substituted with 0-2 R⁶, naphthyl    substituted with 0-2R⁶, and a 5-10 membered heteroaryl system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R⁶ wherein the heteroaryl is selected from indolyl,    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,    benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,    benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,    indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl,    oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl,    pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl,    and tetrazolyl;-   R² is selected from phenyl substituted with 0-2 R⁷, and a 5-10    membered heteroaryl system containing 1-4 heteroatoms selected from    N, O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is    selected from indolyl, benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl,    pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl,    quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(t)SH,    (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),    (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e)    wherein C₂₋₆ is selected from ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl and hexyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-4 R^(4e) wherein the carbocyclic residue    is selected from cyclopropyl, cyclohexyl, and phenyl;-   R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl;-   R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl; and-   R⁸ is selected from H, methyl, ethyl, propyl, i-propyl, and    cyclopropyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹ is selected from phenyl substituted with 0-2 R⁶, naphthyl    substituted with 0-2 R⁶, and a 5-10 membered heteroaryl system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R⁶ wherein the heteroaryl is selected from indolyl,    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,    benzthiazolyl, benzo[b]thiophene, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl,    isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,    pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,    pyrimido[5,4-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,    pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl;-   R² is selected from phenyl substituted with 0-2 R⁷, and a 5-10    membered heteroaryl system containing 1-4 heteroatoms selected from    N, O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is    selected from indolyl, benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benzo[b]thiophene,    benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,    benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,    indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,    phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,    pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(t)SH,    (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),    (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e)    wherein C₂₋₆ is selected from ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl and hexyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-4 R^(4e) wherein the carbocyclic residue    is selected from cyclopropyl, cyclohexyl, and phenyl;-   R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl;-   R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl; and-   R⁸ is selected from H, methyl, ethyl, propyl, i-propyl, and    cyclopropyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)OH, (CRR)_(r)O(CRR)_(r)R^(6d),    (CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(6d),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)(CRR)_(r)R^(6b),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)NR^(6f)C(O)(CRR)_(r)R^(6b),    (CRR)_(r)C(O)O(CRR)_(r)R^(6d), (CRR)_(r)NR^(6a)C(O)NR^(6a)R^(6a),    (CRR)_(r)NR^(6a)C(s)NR^(6a)R^(6a), (CRR)_(r)OC(O)(CRR)_(r)R^(6b),    (CRR)_(r)S(O)_(p)(CRR)_(r)R^(6b), (CRR)_(r)S(O)₂NR^(6a)R^(6a),    (CRR)_(r)NR^(6f)S(O)₂(CRR)_(r)R^(6b), (CRR)_(r)NR^(6f)S(O)₂    NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CRR)_(r)phenyl substituted with    0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system    containing 1-2 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,    hexyl, cyclopropyl and phenyl;-   R^(6b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and    phenyl;-   R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, t-butyl, pentyl, hexyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CRR)_(r)NR^(7a)R^(7a), (CRR)_(r)OH,    (CRR)_(r)O(CH)_(r)R^(7d), (CRR)_(r)SH, (CRR)_(r)C(O)H,    (CRR)_(r)S(CRR)_(r)R^(7d), (CRR)_(r)C(O)OCH,    (CRR)_(r)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)NR^(7a)R^(7a),    (CRR)_(r)NR^(7f)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)O(CRR)_(r)R^(7d),    (CRR)_(r)OC(O)(CRR)_(r)R^(7b), (CRR)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CRR)_(r)NR^(7a)C(O)O(CRR)_(r)R^(7d),    (CRR)_(r)S(O)_(p)(CRR)_(r)R^(7b), (CRR)_(r)S(O)₂NR^(7a)R^(7a),    (CRR)_(r)NR^(7f)S(O)₂(CRR)_(r)R^(7b), C₁₋₆ haloalkyl, and    (CRR)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, CH₂cyclopropyl, and benzyl;-   R^(7b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,    cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,    pyrrolidinyl, morpholinyl, piperizinyl substituted with 0-1 R^(7e),    and azetidinyl;-   R^(7d), at each occurrence, is selected from methyl, CF₃, CF₂CF₃,    CH₂F₂, CH₂F, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,    pentyl, hexyl, and cyclopropyl;-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, C(O)OC₁₋₅ alkyl,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl; and-   r is 0 or 1.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)R^(6a),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6f)S(O)₂    NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted    with 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system    containing 1-2 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,    hexyl, cyclopropyl and phenyl;-   R^(6b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and    phenyl;-   R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, t-butyl, pentyl, hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CH)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, adamantyl,    and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, CH₂cyclopropyl, and benzyl;-   R^(7b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,    cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,    pyrrolidinyl, morpholinyl, piperizinyl substituted with 0-1 R^(7e),    and azetidinyl;-   R^(7d), at each occurrence, is selected from methyl, CF₃, CF₂CF₃,    CHF₂, CH₂F, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,    pentyl, hexyl, and cyclopropyl;-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, C(O)OC₁₋₅ alkyl,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl; and-   r is 0 or 1.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,    CHF₂, CH₂F, OCF₃, C(O)R^(7b), C(O)OR^(7d), NR^(7f)C(O)N^(7a)R^(7a),    NHS(O)₂R^(7b),

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,    CHF₂, CH₂F, OCF₃, C(O)R^(7b), C(O)OR^(7d), NR^(7f)C(O)NR^(7a)R^(7a),    NHS(O)₂R^(7b), adamantyl,

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being optionally substituted with 0-1 R⁵;-   Z is selected from a bond, —NR⁸C(O)—, —C(O)NH—, and —NHC(O)NH—;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is selected from phenyl and naphthyl, and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N and O, substituted with 0-3 R⁶ wherein the heteroaryl system    is selected from indolyl and pyridinyl;-   R² is phenyl substituted with 0-2 R⁷;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, hexyl, and (CH₂)_(r)C(O)R^(4b);-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl,    Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H, C(O)R^(6d), C(O)OH,    SR^(6d), NR^(6a)R^(6a), NC(O)R^(6b), OC(O)R^(6b), S(O)_(p)R^(6b),    (CHR′)_(r)S(O)₂NR^(6a)R^(6a), and CF₃;-   R^(6a) is H, methyl, or ethyl;-   R^(6b) is H, methyl, ethyl, propyl, i-propyl or butyl;-   R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl; and-   r is 0 or 1.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is selected from phenyl and naphthyl, and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N and O, substituted with 0-3 R⁶ wherein the heteroaryl system    is selected from indolyl, pyridinyl, pyrimidinyl,    pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, imidazolyl, and    pyrrolyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being substituted with 0-1 R⁵;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is selected from phenyl, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N and O,    substituted with 0-3 R⁶ wherein the heteroaryl system is selected    from indolyl and pyridinyl;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, hexyl, allyl and (CH₂)_(r)C(O)R^(4b);-   R⁵ is selected from H, OH, OCH₃, and NR^(5a)R^(5a);-   R^(5a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl,    cyclopropyl, cyclopropylmethyl, acetyl, methylsulfonyl, —C(O)CF₃,    C(═N)NH₂, benzyl, and —C(O)O-t-butyl;-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, vinyl,    F, Cl, Br, I, CN, NR^(6a)R^(6a), C(O)H, C(O)OH, C(O)R^(6b), SR^(6d),    S(O)_(p)R^(6d), S(O)₂NR^(6a)R^(6a), CF₃, and CH₂OH;-   R^(6b) is H, methyl, ethyl, propyl, i-propyl or butyl;-   R^(6d) is methyl;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,    CHF₂, CH₂F, OCF₃, OCF₂CF₃, OCHF₂ and OCH₂F, C(O)OR^(7d), C(O)R^(7b),    NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl;-   R^(7b) is selected from cyclohexyl and CF₃; and-   R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, and t-butyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being substituted with 0-1 R⁵;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is selected from phenyl, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N and O,    substituted with 0-3 R⁶ wherein the heteroaryl system is selected    from indolyl and pyridinyl;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, hexyl, allyl and (CH₂)_(r)C(O)R^(4b);-   R⁵ is selected from H, OH, OCH₃, N(→O)R^(5a)R^(5a), N₃,    NR^(5a)C(O)R^(5b), NR^(5a)C(O)H, NR^(5a)C(O)OR^(5d),    NR^(5a)C(O)NR^(5a)R^(5a), and NR^(5a)R^(5a), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-2 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(5e), wherein the    heterocyclic system is selected from pyrrolidinyl, piperidinyl,    pyrrolidin-2-one, and isothiazolidine 1,1-dioxide;-   R^(5a) is selected from H, methyl substituted with 0-1 R^(5g), ethyl    substituted with 0-1 R^(5e), propyl, i-propyl, butyl, s-butyl,    i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl, cyclopropyl,    cyclopropylmethyl, phenyl, benzyl, pyridin-3-yl, thiazolyl;-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, vinyl,    F, Cl, Br, I, CN, NR^(6a)R^(6a), C(O)H, C(O)OH, C(O)R^(6b), SR^(6d),    S(O)_(p)R^(6d), S(O)₂NR^(6a)R^(6a), CF₃, and CH₂OH;-   R^(6b) is H, methyl, ethyl, propyl, i-propyl or butyl;-   R^(6d) is methyl;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, t-butyl, pentyl, hexyl, phenyl, adamantyl, benzyl, Cl, Br,    I, F, CN, NO₂, NR^(7a)R^(7a), OR^(7d), NHC(O)NHR^(7a),    NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F,    OCF₃, OCF₂CF₃, OCHF₂, and OCH₂F, C(O)OR^(7d), C(O)R^(7b),    NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl;-   R^(7b) is selected from cyclohexyl and CF₃; and-   R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, and t-butyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being substituted with 0-1 R⁵;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is phenyl, and a 5-10 membered heteroaryl    system containing 1 heteroatoms selected from N and O, substituted    with 0-3 R⁶ wherein the heteroaryl system is indolyl;-   R⁵ is selected from H, OH, OCH₃, and NR^(5a)R^(5a);-   R^(5a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl,    cyclopropyl, cyclopropylmethyl, acetyl, methylsulfonyl, —C(O)CF₃,    C(═N)NH₂, benzyl, and —C(O)O-t-butyl;-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, Cl, Br, CN,    C(O)CH₃, C(O)OH, OCH₃, NR^(6a)R^(6a), SCH₃, S(O)₂NR^(6a)R^(6a), and    CF₃;-   R^(6a) is H, methyl, ethyl, propyl, i-propyl, butyl, propargyl,    cyclopropyl, allyl;-   R⁷ is selected from Cl, Br, CN, NR^(7a)R^(7a), CF₃, CF₂CF₃, CHF₂,    CH₂F, OCF₃, OCF₂CF₃, OCHF₂, and OCH₂F; and-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   ring B is selected from-    ring B being substituted with 0-1 R⁵;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is phenyl;-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, F, Cl, Br, CN,    SCH₃, and CF₃;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, t-butyl, pentyl, hexyl, phenyl, adamantyl, benzyl, Cl, Br,    I, F, CN, NO₂, NR^(7a)R^(7a), OR^(7d), NHC(O)NHR^(7a),    NR^(7a)C(O)R^(7b), NR^(7a)C(O)COR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F,    OCF₃, OCF₂CF₃, OCHF₂, and OCH₂F, C(O)OR^(7d), C(O)R^(7b), and    NR^(7f)C(O)NR^(7a)R^(7a);-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

E is selected from —CH₂—NH—, —C(O)—NH— and —SO₂—CH₂—.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:B is

ring B being substituted with 0-1 R⁵; and

-   R⁵ is selected from H and NR^(5a)R^(5a);-   R^(5a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    s-butyl, i-butyl, t-butyl, pentyl, hexyl, propargyl, allyl,    cyclopropylmethyl, cyclopropyl, and phenyl.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   Z is selected from a bond, NR⁸C(O)—, —C(O)NH—, and —NHC(O)—.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, vinyl,    F, Cl, Br, I, C(O)H, C(O)R^(6b), SR^(6d), S(O)_(p)R^(6d), CF₃, and    CH₂OH;-   R^(6b) is H, methyl, ethyl, propyl, i-propyl or butyl;-   R^(6d) is methyl;-   R⁷ is selected from Cl, Br, NR^(7a)R^(7a), NR^(7a)C(O)OR^(7d),    NHC(O)NHR^(7a), OCF₃, and CF₃;-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl;-   R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, and t-butyl.

In another embodiment, the present invention provides novel compounds offormula (Ia) or (Ic), wherein:

In another embodiment, the present invention provides novel compounds offormula (Ib), wherein:

In another embodiment, the present invention provides novel compounds offormula (I), wherein the compound is selected from the compounds of theexamples.

In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR-2 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that ismediated by the CCR2 receptor comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),said disorders being selected from osteoarthritis, aneurism, fever,cardiovascular effects, Crohn's disease, congestive heart failure,autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis,idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically-or chemically-induced brain trauma, inflammatory bowel disease,alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serumnephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, rheumatoid arthritis, restinosis, organtransplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, of Formula (I), wherein said disorders beingselected from psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis,restinosis, organ transplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, of Formula (I), wherein said disorders beingselected from alveolitis, colitis, systemic lupus erythematosus,nephrotoxic serum nephritis, glomerularnephritis, asthma, multiplesclerosis, artherosclerosis, and rheumatoid arthritis, restinosis, organtransplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, of Formula (I), wherein said disorders beingselected from asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating disorders, of Formula (I), wherein said disorders beingselected from restinosis, organ transplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating rheumatoid arthritis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating multiple sclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating atherosclerosis, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating asthma, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating restinosis, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating organ transplantation, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating cancer, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating inflammatory diseases, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating inflammatory diseases which are at least partially mediated byCCR-2, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed the use of acompound of Formula (I) in the preparation of a medicament for thetreatment of osteoarthritis, aneurism, fever, cardiovascular effects,Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a compoundof formula (I) for use in therapy.

In another embodiment, the present invention is directed to a compoundof formula (Ia)

In another embodiment, the present invention is directed to a compoundof formula (Ib)

In another embodiment, the present invention is directed to a compoundof formula (Ic)

In another embodiment, ring B is selected from

-   -   ring B being optionally substituted with 0-1 R⁵.        In another embodiment, ring B is selected from        In another embodiment, ring B is selected from    -   ring B being substituted with 0-1 R⁵;

-   In another embodiment, ring B is

-    ring B being substituted with 0-1 R⁵;

-   In another embodiment, E is —S(O)_(p)CH₂—

-   In another embodiment, E is —C(O)NH—.

-   In another embodiment, E is —CH₂NH—.

-   In another embodiment, Z is selected from a bond, —NR⁸C(O)—,    —NR⁸C(O)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —C(O)NR⁸—, —(CR¹⁵R¹⁵)_(l)—,    —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—, —C(O)CR¹⁵R¹⁵—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—,    —O—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—,    —S(O)_(p)—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—.

-   In another embodiment, Z is selected from a bond, —NR⁸C(O)—,    —NR⁸C(O)NH—, —C(O)NR⁸—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁵R¹⁵C(O)—,    —C(O)CR¹⁵R¹⁵—, O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—, and —S(O)—NR⁹—.

-   In another embodiment, Z is selected from a bond, —NR⁸C(O)—,    —NR⁸C(O)NH—, and —C(O)NR⁸—.

-   In another embodiment, Z is selected from a bond, —NR⁸C(O)—,    —C(O)NH—, and —NHC(O)NH—.

-   In another embodiment, Z is selected from —C(O)NH—.

-   In another embodiment, Z is selected from a bond, and —NHC(O)—;

-   In another embodiment, Z is a bond.

-   In another embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CHR)_(s)SH, (CRR)_(t)OR^(4d),    (CHR)_(t)SR^(4d), (CHR)_(t)NR^(4a)R^(4a), (CHR)_(q)C(O)OH,    (CHR)_(r)C(O)R^(4b), (CHR)_(r)C(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CHR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CHR)_(r)S(O)_(p)R^(4b),    (CHR)_(r)S(O)₂ NR^(4a)R^(4a), (CHR)_(r)NR^(4a)S(O)₂R^(4b); and

-   R, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(6e).

-   In another embodiment, R⁴ is selected from H, methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(t)SH,    (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),    (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)N^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b).

-   R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl; and

-   R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl.

-   In another embodiment, R⁴ is selected from H, methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)C(O)R^(4b).

-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d),    (CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)N(O)R^(5a)R^(5a), N₃,    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)NR^(5a)C(O)OR^(5d),    (CRR)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl.

-   In another embodiment, R⁵ is selected from H, OH, OCH₃,    N(→O)R^(5a)R^(5a), N₃, NR^(5a)C(O)R^(5b), NR^(5a)C(O)H,    NR^(5a)C(O)OR^(5d), NR^(5a)C(O)NR^(5a)R^(5a), and NR^(5a)R^(5a), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(5e),    wherein the heterocyclic system is selected from pyrrolidinyl,    piperidinyl, pyrrolidin-2-one, and isothiazolidine 1,1-dioxide;

-   R^(5a) is selected from H, methyl substituted with 0-1 R^(5g), ethyl    substituted with 0-1 R^(5e), propyl, i-propyl, butyl, s-butyl,    i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl, cyclopropyl,    cyclopropylmethyl, phenyl, benzyl, pyridin-3-yl, thiazolyl.

-   In another embodiment, R⁵ is selected from H, N(→O)R^(5a)R^(5a), N₃,    NR^(5a)C(O)R^(5b), NR^(5a)C(O)H, NR^(5a)C(O)OR^(5d),    NR^(5a)C(O)NR^(5a)R^(5a), and NR^(5a)R^(5a), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-2 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(5e), wherein the    heterocyclic system is selected from pyrrolidinyl, piperidinyl,    pyrrolidin-2-one, and isothiazolidine 1,1-dioxide.

-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(5d), (CH₂)_(r)SR^(5d),    (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)N(O)R^(5a)R^(5a), N₃,    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)NR^(5a)C(O)OR^(5d),    (CH₂)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)H, (CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)S(O)₂NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl.

-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    allyl, propynyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(5d),    (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),    (CH₂)_(r)C(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)R^(5b),    (CH₂)_(r)OC(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)OR^(5d),    (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)C(O)OR^(5b),    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆    haloalkyl; and

-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,    cyclopropyl, and cyclobutyl.

-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, OH, OR^(5d), (CH₂)_(r)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)R^(5b), and (CH₂)_(r)NR^(5a)C(O)OR^(5d).

-   In another embodiment, R¹ is selected from phenyl substituted with    0-2 R⁶, naphthyl substituted with 0-2 R⁶, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N, O, and    S, substituted with 0-3 R⁶ wherein the heteroaryl is selected from    indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl.

-   In another embodiment, R¹ is selected from a C₆₋₁₀ aryl group    substituted with 0-3 R⁶ wherein the aryl group is selected from    phenyl and naphthyl, and a 5-10 membered heteroaryl system    containing 1-4 heteroatoms selected from N and O, substituted with    0-3 R⁶ wherein the heteroaryl system is selected from furanyl,    indolyl, benzothiazolyl, and benzotriazolyl.

-   In another embodiment, R¹ is selected from phenyl substituted with    0-2 R⁶, naphthyl substituted with 0-2 R⁶, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N, O, and    S, substituted with 0-3 R⁶ wherein the heteroaryl is selected from    indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benzo[b]thiophene, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl,    isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,    pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,    pyrimido[5,4-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,    pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl.

-   In another embodiment, R¹ is selected from a C₆₋₁₀ aryl group    substituted with 0-3 R⁶ wherein the aryl group is selected from    phenyl and naphthyl, and a 5-10 membered heteroaryl system    containing 1-4 heteroatoms selected from N and O, substituted with    0-3 R⁶ wherein the heteroaryl system is selected from indolyl,    pyridinyl, pyrimidinyl, pyrido[2,3-d]pyrimidinyl,    thieno[3,2-d]pyrimidinyl, imidazolyl, and pyrrolyl.

-   In another embodiment, R¹ is selected from a C₆₋₁₀ aryl group    substituted with 0-3 R⁶ wherein the aryl group is selected from    phenyl, and a 5-10 membered heteroaryl system containing 1-4    heteroatoms selected from N and O, substituted with 0-3 R⁶ wherein    the heteroaryl system is selected from indolyl and pyridinyl.

-   In another embodiment, R¹ is selected from a C₆₋₁₀ aryl group    substituted with 0-3 R⁶ wherein the aryl group is phenyl.

-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R⁷    wherein the heteroaryl is selected from benzimidazolyl,    benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,    benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,    benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,    indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,    pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,    pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and    tetrazolyl.

-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷.

-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R⁷    wherein the heteroaryl is selected from indolyl, naphthalenyl,    phthalazinyl, cinnolinyl, quinolinyl, isoquinolinyl, indazolyl, and    quinazolinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benzisoxazolyl, and benzisothiazolyl.

-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R⁷    wherein the heteroaryl is selected from indolyl, benzimidazolyl,    benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,    benzo[b]thiophene, benztriazolyl, benztetrazolyl, benzisoxazolyl,    benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,    indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl,    oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,    pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl.

-   In another embodiment, Z is a bond and R² is selected from a 5-10    membered heteroaryl system containing 1-4 heteroatoms selected from    N, O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is    selected from indolyl, naphthalenyl, phthalazinyl, cinnolinyl,    quinolinyl, isoquinolinyl, indazolyl, and quinazolinyl,    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,    benzthiazolyl, benzisoxazolyl, and benzisothiazolyl.

-   In another embodiment, R⁶, at each occurrence, is selected from C₁₋₈    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH,    (CH₂)_(r)O(CH₂)_(r)R^(6d), (CH₂)_(r)SH, (CH₂)_(r)C(O)H,    (CH₂)_(r)S(CH₂)_(r)R^(6d), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a),    (CH₂)_(r)NR^(6f)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)O(CH₂)_(r)R^(6d),    (CH₂)_(r)OC(O)(CH₂)_(r)R^(6b), (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6b),    (CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6f)S(O)₂(CH₂)_(r)R^(6b),    (CH₂)_(r)NR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(6e);

-   R^(6a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,    hexyl, cyclopropyl and phenyl;

-   R^(6b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and    phenyl;

-   R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;

-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; and

-   R^(6f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl.

-   In another embodiment, R⁶ is selected from methyl, ethyl, propyl,    i-propyl, butyl, F, Cl, Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H,    SR^(6d), NR^(6a)R^(6a), OC(O)R^(6b), S(O)_(p)R^(6b),    (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃;

-   R^(6a) is H, methyl, or ethyl;

-   R^(6b) is H or methyl; and

-   R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl.

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CH₂)_(r)NR^(7a)R^(7a), (CH₂)_(r)OH, (CH₂)_(r)O(CH)_(r)R^(7d),    (CH₂)_(r)SH, (CH₂)_(r)C(O)H, (CH₂)_(r)S(CH₂)_(r)R^(7d),    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)C(O)NR^(7a)R^(7a), (CH₂)_(r)NR^(7f)C(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)C(O)O(CH₂)_(r)R^(7d), (CH₂)_(r)OC(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CH₂)_(r)NR^(7a)C(O)O(CH₂)_(r)R^(7d),    (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(7b), (CH₂)_(r)S(O)₂NR^(7a)R^(7a),    (CH₂)_(r)NR^(7f)S(O)₂(CH₂)_(r)R^(7b), C₁₋₆ haloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(7e);

-   R^(7a), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and    cyclopropyl;

-   R^(7b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;

-   R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and    cyclopropyl;

-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; and

-   R^(7f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl.

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂,    NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),    NR^(7a)C(O)OR^(7d), CF₃, OCF₃, C(O)R^(7b), NR^(7f)C(O)NHR^(7a), and    NHS(O)₂R^(7b).

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,    (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CH)_(r)R^(7d),    (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, adamantyl,    and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e).

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, CN,    NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),    NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F, OCF₃, C(O)R^(7b),    C(O)OR^(7d), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b), adamantyl,

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, phenyl,    adamantyl, benzyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a), OR^(7d),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,    CHF₂, CH₂F, OCF₃, OCF₂CF₃, OCHF₂, and OCH₂F, C(O)OR^(7d),    C(O)R^(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl;

-   R^(7b) is selected from cyclohexyl and CF₃; and

-   R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, and t-butyl.

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, phenyl,    adamantyl, benzyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a), OR^(7d),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,    CHF₂, CH₂F, OCF₃, OCF₂CF₃, OCHF₂, and OCH₂F, C(O)OR^(7d),    C(O)R^(7b), and NR^(7f)C(O)NR^(7a)R^(7a);

-   R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,    cyclopentyl, and cyclohexyl.

-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂,    NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),    NR^(7a)C(O)OR^(7d), CF₃, OCF₃, C(O)OR^(7d), C(O)R^(7b),    NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

-   In another embodiment, R^(7a) is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl,    cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

-   R^(7b) is selected from cyclohexyl and CF₃; and

-   R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, and t-butyl,

-   In another embodiment, R⁸ is H.

-   In another embodiment, R¹¹ and R¹² are H.

-   In another embodiment, if ring B is not substituted with at least    one R⁵ which is to —NR^(5a)R^(5a), than Z must be —NR⁸C(O)— or    —NR⁸C(O)NH—.

-   In another embodiment, the present invention is directed to    compounds of formula (II) which are useful as intermediates is the    preparation of compounds of formula (I), wherein    W is H or I.

-   In another embodiment, the present invention is directed to    compounds of formula (III) which are useful as intermediates in the    preparation of compounds of formula (I), wherein    X, Z, R², R¹³, and n are as described above.

-   In another embodiment, the present invention is directed to process    of preparing compounds of formula (II), wherein    W is H or I;    comprising converting a compound of formula (IV)

-   into a compound of formula (II) by use of an electrophile and base.

-   In another embodiment, the present invention is directed to process    of preparing a compound of formula (III),    X, Z, R², R¹³, and n are as described above, comprising converting a    compound of formula (IV)

-   into a compound of formula (II) by use of an electrophile and base.

-   In another embodiment, the present invention is directed to process    of preparing compounds of formula (I), comprising    converting a compound of formula (IV)

-   into a compound of formula (II) by use of an electrophile and base

-   In another embodiment, the present invention is directed to process    of preparing compounds of formula (I), comprising    converting a compound of formula (IV)

-   into a compound of formula (II) by use of an electrophile and base,    wherein the base is Butyl lithium and the electrophile is iodine

In another embodiment, the present invention is directed compound ofFormula (II)

or salt or stereoisomer thereof, whereinW is selected from H, I, and Br;Pg, at each occurrence, is independently selected from an amineprotecting group.

In another embodiment, the present invention is directed to a compoundof formula (II), wherein

W is selected from H, I, and Br; and

-   Pg, at each occurrence, is independently selected from    benzyloxycarbonyl (Cbz) and tert-butyloxycarbonyl (Boc).

In another embodiment, the present invention is directed to a process ofpreparing a compound of formula (Ia),

or salt or stereoisomer thereof: wherein

-   E is selected from —S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—,    —C(O)—NR^(e)—, —NR^(e)C(O)NR^(e), —SO₂—NR^(e)—, and    NR^(e)SO₂NR^(e)—;-   R^(e) is independently selected from H and C₁₋₃ alkyl;-   X is selected from O or S;-   Z is selected from a bond, —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—,    —NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —C(O)NR⁸—, —OC(O)NR⁸—,    —NR⁸C(O)O—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—,    —C(O)CR¹⁵R¹⁵—, CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—,    —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—;-   wherein neither Z nor R¹³ are connected to a carbon atom labeled    (b);-   bond (a) is a single or double bond;-   alternatively, when n is equal to 2, two atoms labeled (b) may join    through a double bond;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁵, at each occurrence, is independently selected from H,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d),    (CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)N(→O)R^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), and    a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c);-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),    (CH₂)rOC(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b),    (CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(5e);-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(5e);-   R^(e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), —CN, and (CH₂)_(r)phenyl;-   R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(5e);-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R⁶ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl substituted    with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈    alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with    0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),    —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R⁷, at each occurrence, is selected from C₁₋₁₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)C₃₋₁₀ carbocyclic residue and (CR′R′)_(r)phenyl    substituted with 0-3 R^(7e);-   alternatively, two R⁷ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted    with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3    R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-3    R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, C(O)OC₁₋₅ alkyl,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(6e);-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H, and    —C(O)—C₁₋₄alkyl;-   R¹⁰ is independently selected from H, and C₁₋₄alkyl substituted with    0-1 R^(10b), alternatively, two R¹⁰ form ═O;-   R^(10b), at each occurrence, is independently selected from —OH,    —SE, —NR^(10c)R^(10c), —C(O)N^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H and    C₁₋₄alkyl,-   alternatively, two R¹⁴s, along with the carbon atom to which they    are attached, join to form a C₃₋₆ carbocyclic ring;-   R¹⁵, at each occurrence, is independently selected from H,    C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(15a)R^(15a),    C(O)NR^(15a)R^(15a), NR^(15a)C(O)R^(15b), NR^(15a)C(O)OR^(15d),    OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d);-   alternatively, two R¹⁵s, along with the carbon atom or atoms to    which they are attached, join to form a C₃₋₆ carbocyclic ring;-   R^(15a), at each occurrence, is independently selected from H, and    C₁₋₄ alkyl;-   R^(15b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R^(15d), at each occurrence, is independently selected from C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   R¹⁶ is selected from C₁₋₄ alkyl;-   l is selected from 1, 2 and 3;-   n is selected from 0, 1, 2, and 3;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   s is selected from 0 and 1; and-   t, at each occurrence, is independently selected from 2, 3, and 4;    the steps comprising reacting a compound of Formula IV,-   with an electrophile and base to give a compound of Formula II;    wherein    W is selected from H, I, and Br;-   Pg, at each occurrence, is independently selected from an amine    protecting group;-   reacting a compound of Formula II to give the compound of Formula    (Ia).

In another embodiment, the present invention is directed to a process ofpreparing a compound of Formula (II), wherein

or salt or stereoisomer thereof,comprising reacting a compound of Formula (IV)

with an electrophile and a base,whereinW is selected from I and Br;Pg, at each occurrence, is independently selected from an amineprotecting group.

In another embodiment, the present invention is directed to a process ofpreparing a compound of Formula (II), wherein

-   the electrophile is selected from iodine, bromine,    N-bromo-succimide, and N-iodosuccinimide; and-   the base is selected from n-butyl lithium, lithium diisopropylamide    (LDA), sodium hydride, lithium bis(trimethylsilyl)amide, potassium    bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)-amide, and    Li—Al(O-tButyl)₄.

In another embodiment, the present invention is directed to a process ofpreparing a compound of Formula (IIa), wherein

comprising reduction of a compound of Formula (II) with a reducingagent;

wherein W is selected from I and Br, andPg, at each occurrence, is independently selected from an amineprotecting group.

In another embodiment, the present invention is directed to a process ofpreparing a compound of Formula (IIa), wherein the reducing agent isselected from tris-(trimethylsilyl)silane, zinc metal, tributyltinhydride and AIBN.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment are meant to be combined withany and all other elements from any of the embodiments to describeadditional embodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The processes of the present invention are contemplated to be practicedon at least a multigram scale, kilogram scale, multikilogram scale, orindustrial scale. Multigram scale, as used herein, is preferably thescale wherein at least one starting material is present in 10 grams ormore, more preferably at least 50 grams or more, even more preferably atleast 100 grams or more. Multikilogram scale, as used herein, isintended to mean the scale wherein more than one kilogram of at leastone starting material is used. Industrial scale as used herein isintended to mean a scale which is other than a laboratory scale andwhich is sufficient to supply product sufficient for either clinicaltests or distribution to consumers.

Suitable ether solvents include, but are not intended to be limited to,dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan,diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethylether, diethylene glycol dimethyl ether, diethylene glycol diethylether, triethylene glycol dimethyl ether, or t-butyl methyl ether.Suitable hydrocarbon solvents include, but are not intended to belimited to, benzene, cyclohexane, pentane, hexane, toluene,cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, orp-xylene, octane, indane, nonane, or naphthalene.

As used herein, the term “amine protecting group” (or “N-protected”)refers to any group known in the art of organic synthesis for theprotection of amine groups. As used herein, the term “amine protectinggroup reagent” refers to any reagent known in the art of organicsynthesis for the protection of amine groups which may be reacted withan amine to provide an amine protected with an amine protecting group.The “amine protecting group” should be compatible with other reactionconditions. Such amine protecting groups include those listed in Greeneand Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons,New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: 1) acyl types such as formyl,trifluoroacetyl, and p-toluenesulfonyl; 2) aromatic carbamate types suchas benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls,1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl(Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl(Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl;and 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl andadamantyloxycarbonyl.

Amine protecting groups may include, but are not limited to thefollowing:2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl;2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl;1,1-dimethyl-2,2-dibromoethyloxycarbonyl;1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl;p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl;m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl;p-(dihydroxyboryl benzyloxycarbonyl; m-nitrophenyloxycarbonyl;o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl;3,4-dimethoxy-6-nitrobenzyloxycarbonyl;N′-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl;p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl;2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl;or 2-furanylmethyloxycarbonyl.

A suitable selective reducing agent is a reagent or combination ofreagents which will selectively reduce the W group in the compound ofFormula (II) to a hydrogen without altering the character of the othersubstitutents. Suitable selective reducing agents include, but are notlimited to, tris-(trimethylsilyl)silane, zinc metal, tributyltin hydrideand catalytic versions, see Gregory Fu, Org. Syn. (2002), 78, 239-248which is hereby incorporated by reference, and AIBN(2,2′-Azobisisobutyronitrile).

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such ascamphonic chloride as in Steven D. Young, et al, Antimicrobial Agentsand Chemotheraphy, 1995, 2602-2605.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R¹⁰) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹⁰, then saidgroup may optionally be substituted with up to two R¹⁰ groups and R¹⁰ ateach occurrence is selected independently from the definition of R¹⁰.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, CO, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal”, is intended tomean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxaneand their derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term aromatic heterocyclic system, or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, examples of heteroaryls are indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl.

As used herein, the term “cyclic acetal” or the phrase when twovariables “join to form a cyclic acetal” is intended to mean thesubstituent —O—CH₂—O—.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease an active parent drug of the present invention in vivo when suchprodrug is administered to a mammalian subject. Prodrugs the presentinvention are prepared by modifying functional groups present in thecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds of the present invention wherein a hydroxy, amino, orsulfhydryl group is bonded to any group that, when the prodrug of thepresent invention is administered to a mammalian subject, it cleaves toform a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit MCP-1or effective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used. This will sometimesrequire a judgment to modify the order of the synthetic steps or toselect one particular process scheme over another in order to obtain adesired compound of the invention. It will also be recognized thatanother major consideration in the planning of any synthetic route inthis field is the judicious choice of the protecting group used forprotection of the reactive functional groups present in the compoundsdescribed in this invention. An authoritative account describing themany alternatives to the trained practitioner is Greene and Wuts(Protective Groups In Organic Synthesis, Wiley and Sons, 1999).

A series of compounds of formula 4 can be synthesized as shown inScheme 1. Many cyclic amines 1 are available (Cherney, R. J. PCT02/060859 and PCT 03/075853; and in U.S. Patent Application No.60/362,604, filed Mar. 8, 2002, both of which are hereby incorporated byreference) and can be coupled to acid 2. The resulting amide 3 can becyclized (Freidinger et al., J. Org. Chem. 1982, 47, 104) via theactivated thioether to the desired lactam 4.

A series of compounds of formula 7 can be synthesized as shown in Scheme2. The cyclic amine 1 can be coupled to an appropriate carboxylate toafford amide 5. This material can be cyclized under Mitsunobu conditionsto afford β-lactam 6 (Townsend et al., J. Amer. Chem. Soc. 1990, 112,760). The protecting group can be removed and an appropriate group canbe installed (through coupling or another methodology) to deliver thedesired target 7.

A series of compounds of formula 10 can be synthesized by the methodsshown in Scheme 3. Amine 1 can be coupled to an appropriate carboxylate8. The resulting amide 9 can be cyclized via the aldehyde to afford thetarget 10.

A series of compounds of formula 4 can also be synthesized as shown inScheme 4. Amine 1 can be converted into 12 via a reductive amination.The secondary amine 12 can be cyclized under a variety of conditions togive the target 4.

A series of compounds of formula 16 can be synthesized as shown inScheme 5. Amine 1 can be converted into 14 via a Michael reaction.Treatment of 14 with a phosphonate and base affords 15. This materialcan be cyclized through the carboxylate to give 16.

A series of compounds of formula 21 can be synthesized as shown inScheme 6. The appropriate thioester 17 can be converted into thealdehyde 18. Reductive amination of 1 with 18 gives the secondary amine19. This material can be cyclized through the carboxylate to give 20.The protecting group can be removed and an appropriate R² group can becoupled to afford target 21.

The synthesis of R²=pyrimido[5,4-d]pyrimidin-4-01 is shown in Scheme 7.

Intermediates such as 27 can be saponified and coupled to 20 wherePG=H₂. The bromine can also be removed via hydrogenation, or used inSuzuki-type couplings for further elaboration. The conversion of 27 to28 is performed by the method of Buchwald and Yin, J. Am. Chem. Soc.,(124), 6043, 2002.

The synthesis of R²=quinazolines and their analogs wherein the benzenemoiety can also be replaced by a heterocycle are made by the proceduresillustrated in Schemes 8 and 8a. Note that for clarity, benzoic acidsand derivatives were drawn. However, it is to be understood that thebenzene ring can be replaced with heterocycles. R¹ in Schemes 8 and 8arepresents everything to the left of Z in formula (I) where Z=NH. R² andR³ are the usual substituents found on amines such as H, alkyl, etc.,familiar to one skilled in the art and within the scope of R^(7a) inthis application.

Substituted anthranilic acids in Scheme 8 can be synthesized fromBOC-protected anilines via ortho-directed metallation followed byquenching with CO₂. Bromo or iodo substituted quinazolines in Schemes 8and 8a can undergo Suzuki-type couplings for further elaboration.

Compounds containing a succinimide linker can be synthesized by themethods shown in Scheme 9. Amine 1 is coupled to a protected asparticacid derivative to yield succinimide 47 which can be deprotected andcoupled to a carboxylic acid by the usual means familiar to one skilledin the art to yield the compounds of this invention, 48.

Many core rings 1 have been described (see Cherney PTC WO/03075853 andothers above). Others can be synthesized from anhydride openings or thecorresponding amino esters (52) or acid esters (51) as shown in Scheme10. As described (see Bolm et al. J. Org. Chem. 2000, 65, 6984),anhydride 50 can be opened to the acid ester 51. A Curtius reaction, oranother rearrangement, on the carboxylate of 51 can provide thecarbamate 52. Hydrolysis of the ester gives the acid 53 which can beconverted to the primary amide 54. This primary amide 54 can beconverted in one pot to the bicyclic 57 (through the intermediate 55) ortransformed in a discrete step to acyl carbamate 55 and cyclized withthe use of many different electrophiles and bases (see Taguchi et al. J.Org. Chem. 1997, 62, 7330) to give the bicyclic 57. The carboxylate 53can also undergo cyclizations to the lactone 56. These compounds (56,57, 58) serve as versatile intermediates because they can be opened inmany ways to give substituted rings 59. These substituted rings 59 canthen be incorporated into Schemes 1, 2, 3, 4, 5, 6, and 9 acting ascompound 1.

More generally, compounds 55-58 may be prepared as described in Scheme10a. Compounds of Formula (IV), wherein an amine protecting group is asdescribed above, are converted into compounds of Formula (II) by way ofan electrophile and base in a suitable solvent.

Suitable solvents for the reaction are generally the ether solvents ornon reactive hydrocarbon solvents as described above, or mixturesthereof. In particular, the solvents are selected from THF, toluene, andmixtures thereof. Additional non-reactive solvents such as otheraromatic solvents (e.g., benzene, anisole, or quinoline) can also beused.

Suitable electrophiles for the reaction include, but are not limited to,iodine, bromine, N-bromosuccinimide, N-iodosuccinimide,N-(phenylseleno)phthalimide, and benzenesulfenyl chloride. Suitablebases for the reaction include, but are not limited to, alkyl lithiumsuch as n-butyl lithium, lithium diisopropylamide (LDA), sodium hydride,lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide,sodium bis(trimethylsilyl)amide, Li—Al(O-tButyl)₄.

The reaction may be run at temperatures from about −22° C. to about roomtemperature and alternatively, from about 0° C. to about roomtemperature.

The amine protecting group includes all of those defined above and eachmay be selected independently to allow for differential removal of theprotecting groups from the amine.

Scheme 11 shows how compounds like 59 can be converted into the finalcompounds of interest. A compound like 58 can be reductively opened tocompound 59 (RX=BocHN, R′=HO, Z=H₂, R²=Cbz). Treatment of 59 withMitsunobu-like conditions (ArSSAr and nBu₃P, wherein Ar may be any ofthe substituents described by R¹ in the claims) or substitutionconditions yields compound 60. This can be oxidized a number of ways togive the sulfone 61. Removal of the benzyl carbamate gives the primaryamine 62. This can be incorporated into one of the Schemes 1-6 to afford63. The Boc carbamate can then be removed, and the primary amine can besubstituted in a variety of ways to the desired final compound 64.

In a similar way, Scheme 12 shows how a compound like 58 can beconverted into a final compound of interest by changing the order ofScheme 11. The benzyl carbamate of 58 can be removed to give the primaryamine 65. This can be incorporated into one of the Schemes 1-6 to afford66. The reductive opening of 66 gives 67. Treatment of 67 withMitsunobu-like conditions (ArSSAr and nBu₃P) or substitution conditionsyields compound 68, which can be oxidized to the same compound 63 asabove,

The variables described in the schemes may be the same or different thanthose described in the claims. They are not meant to limit the claims.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “g”for gram or grams, “mg” for milligram or milligrams, “mL” for milliliteror milliliters, “¹H” for proton, “h” for hour or hours, “M” for molar,“min” for minute or minutes, “MHz” for megahertz, “MS” for massspectroscopy, “NMR” for nuclear magnetic resonance spectroscopy, “rt”for room temperature, “tlc” for thin layer chromatography, “EtOAc” forethyl acetate, “v/v” for volume to volume ratio, “aq” for aqueoussolutions. “R” and “S” are stereochemical designations familiar to thoseskilled in the art. Compound names are provided by the program ChemDrawUltra (6.0).

Example 12-{(3S)-1-[(1,2-cis)-2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester

(1a) Cis (±)-(2-amino-cyclohexyl)-carbamic acid benzyl estertrifluoroacetic acid salt (620 mg) (Cherney, R. J. PCT Int Appl. (2000),WO 0260859) was dissolved in DMF (6 mL) prior to the addition of4-methylmorpholine (0.56 mL) and N-Boc-L-Met-OH (512.0 mg). Aftercooling to 0° C., BOP Reagent (907.1 mg) was added. The resultingmixture was warmed to rt and was stirred overnight. EtOAc was addedalong with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl(aq), NaHCO₃ solution (aq), and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated. Flash chromatography of the resultingresidue gave an inseparable mixture of diastereomerscis-[2-(2(S)-tert-butoxycarbonylamino-4-methylsulfanyl-butyrylamino)-cyclohexyl]-carbamicacid benzyl ester (921 mg) which was taken forward. MS found:(M+Na)⁺=502.4.

(1b) A portion (910 mg) of the above derivative (1a) was dissolved inMeI (12 mL). After stirring overnight at rt, the solution wasconcentrated and dried. The resulting material was dissolved in DMF (15mL) and CH₂Cl₂ (15 mL) and cooled to 0° C. prior to the addition of 60%NaH (258.4 mg). After stirring 3 h at rt, EtOAc and brine were added.The EtOAc layer was washed with brine, dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave themixture of diastereomerscis-[1-(2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-yl]-carbamicacid benzyl ester (358 mg). MS found: (M+Na)⁺=454.4.

(1c) A portion (340 mg) of the above derivative (1b) was dissolved inCH₂Cl₂ (2 mL) and cooled to 0° C. prior to the addition of TFA. After 1h at rt, the mixture was concentrated. A portion (270 mg) of theresulting residue was dissolved in DMF (5 mL) prior to the addition of4-methylmorpholine (0.24 mL) and2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (220 mg)(Takagishi et al., Synlett 1992, 360). After cooling to 0° C., BOPReagent (322 mg) was added. The resulting mixture was warmed to rt andwas stirred overnight. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl (aq), NaHCO₃ solution (aq), andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave the mixture ofdiastereomerscis-{2-[1-(2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester (196 mg). MS found: (M+Na)⁺=641.4.

(1d) A portion (180 mg) of the above derivative (1c) was dissolved inMeOH prior to the addition of 10% Pd/C (40 mg). A hydrogen balloon wasadded and the mixture was stirred for 3 h. The Pd/C was filtered off andthe solvent was concentrated to a mixture of diastereomerscis-{2-[1-(2-amino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester (140 mg). MS found: (M+H)⁺=485.4.

(1e) A portion (70 mg) of the above derivative (1d) was dissolved in DMF(5 mL) prior to the addition of 4-methylmorpholine (0.05 mL) and4-(methylthio)benzoic acid (52 mg). After cooling to 0° C., BOP Reagent(77 mg) was added. The resulting mixture was warmed to rt and wasstirred overnight. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl (aq), NaHCO₃ solution (aq), andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave the title mixture ofdiastereomers (76 mg) MS found: (M+H)⁺=635.4.

Example 22-{(3S)-1-[(1,2-cis)2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-amino

(2a) A portion (19 mg) of the above Example 1 was dissolved in CH₂Cl₂ (2mL) and cooled to 0° C. prior to the addition of TFA. After 1 h at rt,the mixture was concentrated and dried. This gave the title compound (17mg). MS found: (M+H)⁺=535.4.

Example 3N-{(3S)-1-[(1S,2R,4R)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(3a) 1,4-Cyclohexanedione mono-ethylene ketal (25 g) was dissolved inTHF and cooled to −78° C. 1M Lithium bis(trimethylsily)amide (160 mL) inTHF was added dropwise. After 30 min, ethyl cyanoformate (15.9 mL) wasadded dropwise. After 60 min, the solution was poured into EtOAc andwater containing ice. The organic layer was washed with water and brinebefore it was dried and concentrated. This crude was filtered through aplug of silica to give the 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylicacid ethyl ester (32.4 g). MS found: (M+H)⁺=228.9

(3b) The above derivative (3a) (36.5 g) was dissolved in toluene (500mL) prior to the addition of (S)-methylbenzyl amine (23 mL) andytterbium (III) triflate (0.37 g). This mixture was stirred at refluxfor 3 h. After cooling to rt overnight, the solvent was removed to agolden oil. This oil was dissolved in acetonitrile (420 ml) prior to theaddition of acetic acid (100 mL) and NaBH(OAc)₃ (67.8 g). The mixturewas stirred for 5 days at rt. The solvent was removed before beingredissolved in CH₂Cl₂. After cooling in an ice bath, 1N NaOH was added(pH=8). The organic layer was washed with brine, dried, filtered, andconcentrated. Flash chromatography of the resulting residue gave8(S)-(1(S)-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7(R)-carboxylicacid ethyl ester (26.2 g): ¹H NMR (CDCl₃, δ ppm, 300 MHz) 1.31 (m, 6H),1.46 (m, 1H), 1.6-1.84 (m, 4H), 2.1 (t, 1H), 2.85 (m, 1H), 3.16 (m, 1H),3.76 (m, 1H), 3.93 (m, 4H), 4.19 (q, 2H), 7.2-7.4 (m, 5H).

(3c) The above derivative (3b) (16.3 g) was dissolved in Et₂O (160 mL)and cooled to 0° C. 1M Lithium aluminum hydride in THF (117.3 mL) wasadded dropwise. After the addition, the solution was stirred for 2 hr at0° C. The reaction was quenched with water (4.4 mL) and then 1N NaOH(17.6 mL). The solids were filtered off through a pad of celite. Thefiltrate was concentrated to an oil. This material was dissolved in MeOH(20 mL) prior to the addition of 20% Pd(OH)₂ (3 g). This solution wasplaced on a Parr apparatus at 50 psi. The solution was mixed overnight.The palladium was filtered off and the solution was concentrated. Theresulting oil was dissolved in THF (160 mL) and water (20 mL) prior tothe addition of triethylamine (8.8 mL). After cooling to 0° C., dibenzyldicarbonate (18.2 g) was added. The solution was warmed to rt and wasstirred overnight. Ethyl acetate was added along with brine. The organiclayer was washed with brine, dried, filtered, and concentrated. Flashchromatography of the resulting residue gave(7R,8S)-(7-hydroxymethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamic acidbenzyl ester (9.8 g). MS found: (M+H)⁺=322.2.

(3d) A portion (100 mg) of the above derivative (3c) was dissolved inTHF (10 mL) prior to the addition of tri-n-butylphosphine (0.86 mL).4-Bromophenyl disulfide (233 mg) was added and the solution was stirredin a 75° C. oil bath. After 5 h, the reaction was cooled to rt and flashchromatography gave(7R,8S)-[7-(4-bromo-phenylsulfanylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamicacid benzyl ester (137 mg). ¹H NMR (CDCl₃, δ ppm, 300 MHz) 1.39 (t, 1H),1.5-1.9 (m, 9H), 2.05 (m, 1H)/2.73 (m, 1H), 3.0 (dd, 1H), 3.93 (m, 4H),4.08 (m, 1H), 4.9 (br d, 1H), 5.1 (s, 2H), 7.17 (d, 2H), 7.36 (m, 7H).

(3e) A portion (2.5 g) of the above derivative (3d) was dissolved inCH₂Cl₂ (100 mL) and cooled to 0° C. prior to the addition 65% m-CPBA(3.1 g). After 2 h, the solution was washed with saturated NaHCO₃solution, brine solution, dried, filtered, and concentrated. Flashchromatography of the resulting residue gave(7R,8S)-[7-(4-bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamicacid benzyl ester (2.59 g). MS found: (M+H)⁺=525.9.

(3f) A portion (2.1 g) of the above derivative (3e) was dissolved in DMF(10 mL) prior to the addition of PdCl₂(PPh₃)₂ (56 mg) and Sn(Me)₄ (0.8mL). The resulting solution was heated in an oil bath at 80° C. Fouraddition portions of Sn(Me)₄ (0.8 mL each) were added over 3 days. Aftercooling, EtOAc and brine were added. The organic layer was washed withbrine, dried, filtered, and concentrated. Flash chromatography of theresulting residue gave(7R,8S)-([7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamicacid benzyl ester (1.0 g). MS found: (M+H)⁺=460.3.

(3g) A portion (1.0 g) of the above derivative (3f) was dissolved inMeOH prior to the addition of 10% Pd/C (120 mg). A hydrogen balloon wasadded and the mixture was stirred for 1.5 h. The Pd/C was filtered offand the solvent was concentrated to(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine(740 mg). MS found: (M+H)⁺=326.3.

(3h) A portion (730 mg) of the above derivative (3g) was dissolved inDMF prior to the addition of 4-methylmorpholine (0.74 mL) andN-Cbz-L-Met-OH (889.8 mg). After cooling to 0° C., BOP Reagent (1.4 g)was added. The resulting mixture was warmed to rt and was stirredovernight. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl (aq), NaHCO₃ solution (aq), and brine. The EtOAcwas dried (MgSO₄), filtered, and concentrated. Flash chromatography ofthe resulting residue gave{(1S)-3-methylsulfanyl-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylcarbamoyl]-propyl}-carbamicacid benzyl ester (1.1 g). MS found: (M+Na)⁺=613.4.

(3i) A portion (330 mg) of the above derivative (3h) was dissolved inMeI (6 mL). After stirring overnight at rt, the solution wasconcentrated and dried. A portion (50 mg) of the resulting material wasdissolved in DMF (1.5 mL) prior to the addition of Cs₂CO₃ (133 mg).After stirring overnight at rt, EtOAc and brine were added. The EtOAclayer was washed with brine, dried (MgSO₄), filtered, and concentrated.Flash chromatography of the resulting residue gave{(3S)-2-oxo-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-pyrrolidin-3-yl}-carbamicacid benzyl ester (19 mg), MS found: (M+Na)⁺=565.3.

(3j) A portion (580 mg) of the above derivative (3i) was dissolved inCH₃CN (10 mL) prior to the addition of 1N HCl (10 mL). The mixture wasstirred in a 60° C. oil bath for 4 h. After cooling the solution wasconcentrated. Flash chromatography of the resulting residue gave{(3S)-2-oxo-1-[(1S,2R)-4-oxo-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-3-yl}-carbamicacid benzyl ester (270 mg). MS found: (M+Na)⁺=521.2.

(3k) The above derivative (3j) (270 mg) was dissolved in Ti(OiPr)₄ (4mL) prior to the addition of isopropylamine (0.4 mL). After 1.5 h, MeOH(7 mL) was added followed by NaBH₄ (57 mg). After 1 h, the reaction wasquenched by the addition of 0.1N NaOH and filtered through celite. Thefiltrate was concentrated to a mixture of diastereomers. Flashchromatography of the resulting mixture gave two diastereomers:({(3S)-1-[(1S,2R,4R)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamicacid benzyl ester (3ka) (59 mg), MS found: (M+H)⁺=542.3; and({(3S)-1-[(1S,2R,45)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamicacid benzyl ester (3kb) (28 mg), MS found: (M+H)⁺=542.4.

(3l) The above derivative (3ka) (57 mg) was dissolved in MeOH (1.3 mL)prior to the addition of 37% formaldehyde in water (53 mg). After 1.5 h,NaBH₃CN (10.4 mg) was added. After 1 h, saturated NaHCO₃ was added andsome of the MeOH was removed. EtOAc was added and the organic layer waswashed with brine, dried, filtered, and concentrated. The resultingresidue was dissolved in MeOH prior to the addition of 5% Pd/BaSO₄ (100mg). A hydrogen balloon was added and the mixture was stirred. Two moreportions (50 mg each) of 5% Pd/BaSO₄ were added. The reaction wasstirred for a total of 3 h. The Pd/BaSO₄ was filtered off and thesolvent was concentrated. The resulting residue was dissolved in DMFprior to the addition of 4-methylmorpholine (34 mg) and3-trifluoromethyl-benzoic acid (32 mg). After cooling to 0° C., HATU (64mg) was added. The resulting mixture was warmed to rt and was stirredovernight. EtOAc was added along with saturated NaHCO₃ solution. TheEtOAc layer was washed with NaHCO₃ solution (aq), dried (MgSO₄),filtered, and concentrated. Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the resulting residue provided thetitle compound (36 mg). MS found: (M+H)⁺=594.3.

Example 4N-{(3S)-1-[(1S,2R,4S)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(4a) Derivative (3kb) (28 mg) was incorporated into Example (3l) to givethe title compound (8.1 mg). MS found: (M+H)⁺=594.3.

Example 5N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(5a) Phenyl disulfide was incorporated into Example 3-step (3d) and step(3f) was skipped to give two diastereomers. The first diastereomer wasthe title compound (12.3 mg). MS found: (M+H)⁺=580.3.

Example 6N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(6a) The second diastereomer from above (5a) was isolated as the titlecompound. MS found: (M+H)⁺=580.3.

Example 7N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(7a) Acetaldehyde was incorporated into Example 5 (in the analogous stepto 3l) to give two diastereomers. The first diastereomer was the titlecompound (30 mg). MS found: (M+H)⁺=594.3.

Example 8N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}3-trifluoromethyl-benzamide

(8a) The second diastereomer from above (7a) was the title compound (7mg) MS found: (M+H)⁺=594.3.

Example 9N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-cyclopropylmethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(9a) Cyclopropanecarboxaldehyde was incorporated into Example 5 (in theanalogous step to 3l) to give the title compound (25 mg). MS found:(M+H)⁺=620.3.

Example 10 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(10a) 1-Methanesulfonyl-4-methylsulfanyl-benzene (3.4 g) was dissolvedin THF (40 mL) and cooled to −78° C. prior to the addition of 1.6 MnBuLi (10.4 mL). After 0.5 h, BF₃. Et₂O (2.1 mL) was added followed bycis (±)-4-(benzyloxy)-1,2-epoxycyclohexane (2.3 g) (Chini et al. J. Org.Chem. 1990, 55, 4265) in THF (20 mL). After an addition 1 h at −78° C.,the solution was warmed to 0° C. After 2 h, the solution was cooled to−78° C. and 1N HCl solution (aq) was added. The solution was warmed tort and EtOAc was added. The organic layer was washed with brine, dried,filtered, and concentrated. Flash chromatography of the resultingresidue gave(±)(1R*,2R*,4S*)-4-benzyloxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexanol(2.9 g) as the major product. MS found: (M+H)⁺=407.1.

(10b) A portion of the above material (1.9 g) was dissolved in CH₂Cl₂(15 mL) and cooled to 0° C. prior to the addition of Et₃N (2 mL) andmethanesulfonyl chloride (0.55 mL). After 1 h, the CH₂Cl₂ was removedand EtOAc was added. This was washed with 1N HCl, saturated NaHCO₃, andbrine. The organic layer was dried, filtered, and concentrated. Thissolid was dissolved in DMSO (20 mL) prior to the addition of NaN₃ (2.35g). This was heated at 80° C. for 18 h. After cooling to 0° C., waterwas added and it was extracted with EtOAc. The organic layer was washedwith brine, dried, filtered, and concentrated. Flash chromatography ofthe resulting residue gave(±)(1S*,2R*,4S*)-4-benzyloxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)-azidocyclohexane(1.4 g). MS found: (M-N₃)⁺=388.5.

(10c) A portion of the above material (1.3 g) was dissolved in CH₂Cl₂(15 mL) and cooled to −78° C. prior to the addition of 1.0M BCl₃ (3.9mL) in CH₂Cl₂. The reaction was stirred at 0° C. for 2 h. After coolingto −78° C., MeOH (8 mL) was added. The reaction was warmed to 0° C. andthen rt. The resulting solution was extracted with CH₂Cl₂. The organiclayer was washed with saturated NaHCO₃ solution (aq), brine, dried,filtered, and concentrated. Flash chromatography of the resultingresidue gave(±)(1S*,2R*,4S*)-4-hydroxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)-azidocyclohexane(1.1 g) MS found: (M−HN₃)⁺=298.1.

(10d) The above material (1.1 g) was dissolved in MeOH (10 mL) prior tothe addition of 5% Pd/BaSO₄ (800 mg). A hydrogen balloon was added andthe solution was stirred for 4.0 h. The palladium was filtered off andthe solution was concentrated to(±)(1S*,2R*,4S*)-4-hydroxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylamine:MS found: (M+H)⁺=316.2. The resulting residue was dissolved in THF (10mL) and water (2 mL) prior to the addition of Et₃N (0.88 mL). This wascooled to 0° C. and Boc₂O (761 mg) was added. The reaction was warmed tort and was stirred overnight. The reaction was quenched with water andEtOAc. The EtOAc layer was washed with 1 N HCl solution, NaHCO₃solution, and brine. The organic layer was dried, filtered, andconcentrated (1.44 g). This material (1.44 g) was dissolved in CH₂Cl₂(15 mL) and cooled to 0° C. prior to the addition of Et₃N (1.3 mL) andmethanesulfonyl chloride (0.37 mL). After 1 h, the CH₂Cl₂ was removedand EtOAc was added. This was washed with 1N HCl, saturated NaHCO₃, andbrine. The organic layer was dried, filtered, and concentrated. Thissolid was dissolved in DMSO (10 mL) prior to the addition of NaN₃ (1.03g). This was heated at 80° C. for 18 h. After cooling to 0° C., waterwas added and it was extracted with EtOAc. The organic layer was washedwith brine, dried, filtered, and concentrated. Flash chromatography ofthe resulting residue gave (±)(1S*,2R*,4R*)-[4-azido-2-(4methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acidtert-butyl ester (1.2 g). MS found: (M+Na+CH₃CN)⁺=504.3.

(10e) A portion of the above material (114 mg) was dissolved in CH₂Cl₂(2 mL) and cooled to 0° C. prior to the addition of TFA (2 mL). Afterthe reaction was warmed to rt over 45 min, it was concentrated anddried. The resulting residue was dissolved in DMF (4 mL) prior to theaddition of HATU (166.7 mg) and N-Boc-α-methyl-dl-Met-OH (101.7 mg).After cooling to 0° C., diisopropylethylamine (0.74 mL) was added. Theresulting mixture was warmed to rt and was stirred overnight beforebeing concentrated. Flash chromatography of the resulting residue gave{1-[4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylcarbamoyl]-1-methyl-3-methylsulfanyl-propyl}-carbamicacid tert-butyl ester (113 mg) as a mixture of diastereomers. MS found:(M+H)⁺=586.5.

(10f) The above derivative was dissolved in MeI (5 mL). After stirringovernight at rt, the solution was concentrated and dried. The resultingmaterial was dissolved in DMF (4 mL) prior to the addition of Cs₂CO₃(380 mg). After stirring overnight the solution was filtered andconcentrated. Flash chromatography of the resulting residue provided thebottom diastereomer (TLC 80% EtOAc/Hex)(±){(3S*)-1-[(1S*,2R*,4R*)-4-azido-2(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (36 mg). MS found: (M+Na)⁺=538.5.

(10g) The above material was dissolved in CH₂Cl₂ (1 mm) and cooled to 0°C. prior to the addition of TFA (1 mL). After the reaction was warmed tort over 30 min, it was concentrated and dried. The resulting residue wasdissolved in CH₂Cl₂ prior to the addition of diisopropylethylamine (0.05mL) and 3-(trifluoromethyl)benzoyl chloride (28 mg). After stirring for1.5 h, the reaction was diluted with CH₂Cl₂ and washed with water, 10%citric acid solution, NaHCO₃ solution, and brine. The CH₂Cl₂ layer wasdried (MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue provided the title compound (24 mg). MS found:(M+H)⁺=610.5.

Example 11 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(11a) Example 10 (20 mg) was dissolved in MeOH (2 mL) prior to theaddition of 5% Pd/BaSO₄ (10 mg). A hydrogen balloon was added and themixture was stirred. After stirring 45 min, the Pd/BaSO₄ was filteredoff and the solvent was concentrated to give the title compound. MSfound: (M+H)⁺=584.5.

Example 12 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Isopropylamino-2(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(12a) Example 11 (16 mg) was dissolved in dichloroethane (1 mL) prior tothe addition of glacial acetic acid (8 mg), acetone (8 mg), andNaBH(OAc)₃ (30 mg). After 20 h, the solution was concentrated. Theresulting residue was dissolved in EtOAc and washed with saturatedNaHCO₃, water, and brine. The organic layer was dried, filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (13 mg). MS found: (M+H)⁺=626.6.

Example 13 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(13a) Example 12 (22 mg) was dissolved in MeOH (1 mL) prior to theaddition of 37% formaldehyde in water (4 mg). After 15 min, NaBH₃CN (4mg) was added. After 1 h, saturated NaHCO₃ was added and some of theMeOH was removed. EtOAc was added and the organic layer was dried,filtered, and concentrated. Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the resulting residue provided thetitle compound (13 mg). MS found: (M+H)⁺=640.6.

Example 14 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-prop-2-ynyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(14a) Example 12 (20 mg) was dissolved in acetonitrile (1 mL) prior tothe addition of K₂CO₃ (22 mg) and propargyl bromide (8 mg). After 4.75 hat 45° C., the reaction was cooled to rt. Saturated NaHCO₃ was added andthe reaction was extracted with EtOAc. The organic layer was dried,filtered, and concentrated. Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the resulting residue provided thetitle compound (7 mg). MS found: (M+H)⁺=664.6.

Example 15 (±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Cyclopropylmethyl-isopropyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(15a) Cyclopropanecarboxaldehyde was incorporated into Example 13 togive the title compound (11 mg). MS found (M+H)⁺=680.6.

Example 16N-{(3S)-1-[4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide

(16a) N(Me)Boc-L-Met-OH was incorporated into Example 10, step (10e),and advanced in an analogous way to Example 12. This procedure gave thetitle compound (31 mg) as a mixture of diastereomers. MS found:(M+H)⁺=640.3.

Example 17N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(17a) N-Boc-L-Met-OH was incorporated into Example 16 to give the titlecompound. MS found: (M+H)⁺=626.3.

Example 181-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea

(18a){(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (350 mg), from the synthesis of Example 17(analogous to 10f), was dissolved in MeOH (5 mL) prior to the additionof 5% Pd/BaSO₄ (300 mg). A hydrogen balloon was added and the mixturewas stirred. After stirring 1 h, the Pd/BaSO₄ was filtered off and thesolvent was concentrated to give{(3S)-1-[(1S,2R,4R)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (497 mg). MS found: (M−H)⁻=496.5.

(18b) A portion of the above material (341 mg) was dissolved indichloroethane (5 mL) prior to the addition of acetone (0.25 mL) andNaBH(OAc)₃ (436 mg). After 2 h, the solution was concentrated. Theresulting residue was dissolved in EtOAc and washed with saturatedNaHCO₃. The organic layer was dried, filtered, and concentrated. Theresulting residue was dissolved in MeOH (2 mL) prior to the addition of37% formaldehyde in water (0.1 mL). After 15 min, NaBH₃CN (111 mg) wasadded. After 2 h, saturated NaHCO₃ was added and some of the MeOH wasremoved. EtOAc was added and the organic layer was dried, filtered, andconcentrated. This material was passed through a plug of silica andconcentrated. This material (300 mg) was dissolved in CH₂Cl₂ (5 mL)prior to the addition of TFA (2.5 mL). After 30 min, it was concentratedand dried. A portion of the resulting residue (35 mg) was dissolved inDMF (1 mL) prior to the addition of 4-methylmorpholine (0.02 mL) and3-trifluoromethylphenyl isocyanate (0.013 mL). After 2 h, the solutionwas concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (7 mg). MS found: (M+H)⁺=641.3.

Example 19N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzenesulfonamide

(19a) 3-(Trifluoromethyl)phenylsulfonyl chloride (instead of3-trifluoromethylphenyl isocyanate) and pyridine (instead of4-methylmorpholine) were incorporated into Example 18 to give the titlecompound. MS found: (M+H)⁺=662.3.

Example 20N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-benzamide

(20a) Benzoic acid was incorporated into Example 17 to give the titlecompound. MS found: (M+H)⁺=558.3.

Example 21{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea

(21a) Example 18 (15 mg) was dissolved in MeOH (1 mL) prior to theaddition of 20% Pd(OH)₂ (20 mg). A hydrogen balloon was added and themixture was stirred. After stirring overnight, the palladium wasfiltered off and the solvent was concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title compound. MS found: (M+H)⁺=595.3.

Example 22N-[(3S)-1-((1S,2R,4R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidin-3-yl]-3-trifluoromethyl-benzamide

(22a){(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (240 mg), see example 18, was dissolved in CH₂Cl₂(5 mL) prior to the addition of TFA (2.5 mL). After 30 min, it wasconcentrated and dried. The resulting residue was dissolved in DMF priorto the addition of 4-methylmorpholine (0.25 mL) and3-trifluoromethyl-benzoic acid (104.5 mg). BOP Reagent (64 mg) was addedand the mixture was stirred for 40 min. After concentration, EtOAc wasadded along with 1N HCl solution. The EtOAc layer was washed with NaHCO₃solution (aq) and brine, dried (MgSO₄), filtered, and concentrated. Thismaterial was passed through a plug of silica and concentrated. Theresulting material (178 mg) was dissolved in MeOH (5 mL) prior to theaddition of 20% Pd(OH)₂ (100 mg). A hydrogen balloon was added and themixture was stirred. After stirring overnight, the palladium wasfiltered off and the solvent was concentrated. A portion of thismaterial (68 mg) was dissolved in dichloroethane (2.5 mL) prior to theaddition of acetone (0.04 mL) and NaBH(OAc)₃ (64 mg). After 40 min, thesolution was concentrated. The resulting residue was dissolved in EtOAcand washed with saturated NaHCO₃. The organic layer was dried, filtered,and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (66 mg). MS found: (M+H)⁺=566.4.

Example 23N-{(3S)-1-[(1S,2R,4R)-4-(Allyl-isopropyl-amino)-2-benzenesulfonylmethyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(23a) Example 22 (17 mg) was dissolved in DMF (1 mL) prior to theaddition of K₂CO₃ (11 mg) and allyl bromide (0.003 mL). After stirringovernight, the reaction was filtered and concentrated. Reverse phaseHPLC purification (gradient elution, water/acetonitrile/TFA) of theresulting residue provided the title compound (5 mg). MS found:(M+H)⁺=606.3.

Example 241-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide

(24a) Phenyl disulfide was incorporated into Example 3, step 3d (inplace of 4-bromophenyl disulfide), and advanced to step 3e to give(7R,8S)-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamicacid benzyl ester. This material (1.2 g) was dissolved in MeOH prior tothe addition of 10% Pd/C (250 mg). A hydrogen balloon was added and themixture was stirred for 5 h. The Pd/C was filtered off and the solventwas concentrated to give(7R,8S)-7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-ylamine (826mg). MS found: (M+H)⁺=312.3.

(24b) A portion of this material (239 mg) was dissolved indichloroethane (4 mL) prior to the addition of3,3-bis(methoxycarbonyl)propanal (160 mg) (Bunce et al. Org. Prep. Proc.Int. 1987, 19, 67-71). The mixture was stirred for 1.5 h beforeNaBH(OAc)₃ (195 mg) was added. After 2 h, EtOAc and saturated NaHCO₃ wasadded. The organic layer was washed with additional saturated NaHCO₃solution. The organic layer was dried, filtered, and concentrated togive(7R,8S)-2-[2-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-ylamino)-ethyl]-malonicacid dimethyl ester (203 mg). MS found: (M+H)⁺=470.4.

(24c) A portion of this material (52 mg) was dissolved in MeOH prior tothe addition of 0.5M NaOMe (0.05 mL) in MeOH. The mixture was stirredovernight before being concentrated. EtOAc and 1N HCl was added. Theorganic layer was washed with additional 1N HCl solution. The organiclayer was dried, filtered, and concentrated to give(1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-pyrrolidine-3-carboxylicacid methyl ester (42 mg) as a mixture of diastereomers. MS found:(M+H)⁺=460.3.

(24d) A portion of this material (110 mg) was dissolved in THF (1 mL),MeOH (0.5 mL), and water (0.5 mL) at 0° C. prior to the addition of 1MLiOH (0.25 mL) in water. The reaction was stirred for 2 h. EtOAc and 1NHCl was added. The organic layer was washed with additional 1N HClsolution. The organic layer was dried, filtered, and concentrated togive1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-pyrrolidine-3-carboxylicacid (105 mg). MS found: (M+H)⁺=424.3.

(24e) This material was dissolved in DMF prior to the addition of4-methylmorpholine (0.08 mL) and 3-(trifluoromethyl)phenyl aniline (0.05mL). HATU (114 mg) was added and the mixture was stirred overnight.EtOAc was added along with 1N HCl solution. The EtOAc layer was washedwith NaHCO₃ solution and brine, dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide. MS found: (M+H)⁺=567.3.

(24f) A portion of this material (118 mg) was dissolved in acetone (1mL) prior to the addition of 1N HCl (4 mL). The mixture was heated atreflux for 3 h. After cooling, the solution was concentrated. Flashchromatography of the resulting residue gave two diastereomers of1-(2-benzenesulfonylmethyl-4-oxo-cyclohexyl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide as top (MS found: (M−H)⁻=521.3)and bottom (MS found: (M+Na)⁺=545.2).

(24g) The above top diastereomer (53 mg) was dissolved in Ti(OiPr)₄(0.74 mL) prior to the addition of isopropylamine (0.08 mL). After 1.5h, MeOH (1.5 mL) was added followed by NaBH₄ (11 mg). After 1 h, thereaction was quenched by the addition of 0.1N NaOH and filtered throughcelite. The filtrate was concentrated to a mixture of diastereomers.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (15 mg) as a mixture of diastereomers. MS found: (M+H)⁺=566.3.

Example 251-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide

(25a) The above bottom diastereomer from 24f (71 mg) was dissolved inTi(OiPr)₄ (0.7 mL) prior to the addition of isopropylamine (0.08 mL).After 1.5 h, MeOH (1.5 mL) was added followed by NaBH₄ (11 mg). After 1h, the reaction was quenched by the addition of 0.1N NaOH and filteredthrough celite. The filtrate was concentrated to a mixture ofdiastereomers. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (22 mg) as a mixture of diastereomers. MS found: (M+H)⁺=566.5.

Example 26(2-{(3S)-1-[(1S,2R)-2-(4-Methylsulfanyl-benzylamino)-cyclohexyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester

(26a) Flash chromatography of the mixture of diastereomers in step (ic)gave the clean bottom isomer as{2-[(3S)-1-((1S,2R)-2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-3-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester (MS found: (M−H)⁻=617.2).

(26b) A portion of this material (50 mg) was dissolved in MeOH (5 mL)prior to the addition of 10% Pd/C (10 mg). A hydrogen balloon was addedand the mixture was stirred for 3 h. The Pd/C was filtered off and thesolvent was concentrated. The resulting residue was dissolved indichloroethane (1.4 mL) prior to the addition of glacial acetic acid(0.009 mL), 4-(methylthio)benzaldehyde (0.02 mL), and NaBH(OAc)₃ (31mg). After 20 h, the solution was concentrated. The resulting residuewas dissolved in EtOAc and washed with saturated NaHCO₃ solution. Theorganic layer was dried, filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title compound (15 mg). MS found: (M+H)⁺=621.4.

Example 27N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4(R)-(isopropyl-propyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide

(27a) Propionaldehyde was incorporated into Example 5 (in the analogousstep to 3l) to give two diastereomers. The first diastereomer was thetitle compound (10 mg). MS found: (M+H)⁺=608.3.

Example 28 (±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one

(28a) Vinylmagnesium bromide (40 mL of a 1.0 M THF solution, 40 mmol)was added to a dry round bottom flask under nitrogen. The solution wascooled to −10° C. and charged with meta-trifluoromethylbenzaldehyde (5.0g, 29 mmol). The reaction was stirred for 1 h, warmed to RT and quenchedwith sat. NH₄Cl. The mixture was extracted with EtOAC three times, andthe organic extracts were dried (MgSO₄) and concentrated in vacuo. Thecrude material was purified via flash chromatography to give1-(3-trifluoromethylphenyl)propen-1-ol as an oil (5.0 g, 87% yield). Aportion of 1-(3-trifluoromethylphenyl)-propen-1-ol (0.5 g, 2.5 mmol) wasdissolved in acetone (20 mL). The resultant solution was cooled to 0°C., treated with Jones reagent (1.14 mL of a 2.6 M solution, 2.96 mmol),and stirred for 10 minutes before being quenched with the addition ofisopropyl alcohol (1.5 mL). The mixture was stirred for 5 min at rt,diluted with Et₂O, filtered through Celite, washed with 10% Na₂SO₃. Thematerial was purified via filtration through a plug of silica gel (1:1Et₂O:hexanes as eluant) to provide the1-(3-trifluoromethylphenyl)propenone as an oil (320 mg, 65% yield),which solidified upon standing in the freezer. ¹H-NMR (300 MHz, CDCl₃):δ 8.20 (s, 1H), 8.13 (d, 1H, J=7.7 Hz), 7.64 (d, 1H, J=9.0 Hz), 7.64 (t,1H, J=7.7 Hz), 7.16 (dd, 1H, J=17.2, 10.6 Hz), 6.49 (dd, 1H, J=17.2, 1.5Hz), 6.03 (dd, 1H, J=10.6, 1.5 Hz).

(28b) The compound (±)[(1S*,2R*,4R*)-4-azido-2(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamicacid tert-butyl ester (2.36 g, 5.36 mmol, see procedure 10d above) wasdissolved in 2:1 CH₂Cl₂/TFA and stirred at rt for 1 h before beingconcentrated in vacuo. The resulting residue was redissolved in 1N NaOHand this solution was extracted twice with Et₂O. The extracts werecombined, washed with brine, dried (MgSO₄), filtered, and concentratedin vacuo. The product amine was dissolved in MeOH (40 mL), cooled to−10° C., and treated with a solution of the1-(3-trifluoromethylphenyl)propenone (1.09 g, 5.23 mmol) in MeOH (10mL). The reaction was stirred for 30 min at rt, diluted with EtOAc, andwashed successively with sat. NaHCO₃ and brine. The organic phase wasdried (MgSO₄), filtered, and concentrated in vacuo. The resultantresidue was purified by flash chromatography to give the desired (±)3-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylamino]-1-(3-trifluoromethyl-phenyl)-propan-1-one(2.0 g, 69% yield). MS found: (M+H)⁺=541.3.

(28c) To a cooled (0° C.) solution of dimethylphosphonoacetic acidtert-butyl ester (0.44 mL, 2.22 mmol) in THF (20 mL) was added sodiumhydride (94 mg, 60 wt % dispersion in oil, 2.35 mmol) in one portion.The mixture was stirred for 30 minutes at O—C and then charged with asolution of (±)3-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylamino]-1-(3-trifluoromethyl-phenyl)-propan-1-one(0.75 g, 1.38 mmol) in THF. The reaction was stirred for 64 h at rt,quenched with sat. NH₄Cl, and extracted twice with EtOAc. The organicextracts were combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude residue was purified by flashchromatography to afford diastereomerically-pure (±)E-[5-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylamino]-3-(3-trifluoromethyl-phenyl)-pent-2-enoicacid tert-butyl ester] (0.26 g, 29% yield) and a number of impurefractions of the same compound contaminated with its Z-diastereomer. MSfound: (M+H)⁺=639.3.

(28d) The compound (±)E-[5-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylamino]-3-(3-trifluoromethyl-phenyl)-pent-2-enoicacid tert-butyl ester] (0.26 g, 0.4 mmol) was dissolved in 2:1CH₂Cl₂/TFA and stirred at rt for 1 h before being concentrated in vacuo.The residue was redissolved in CH₂Cl₂ and concentrated in vacuo; thisprocedure was repeated once. The unpurified amino acid was dissolved inCH₂Cl₂, and the resulting solution was sequentially charged withN,N-diisopropylethylamine (0.3 mL, 1.6 mmol), 4-dimethylaminopyridine(54 mg, 0.44 mmol), and HATU (170 mg, 0.44 mmol). The mixture wasstirred for 14 h at rt, quenched with sat. NH₄Cl, and extracted twicewith EtOAc. The organic extracts were combined, washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude residue waspurified by flash chromatography to afford (±)1-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one(0.2 g, 89% yield). The entirety of this material was dissolved in MeOH.The resultant solution was charged with 0.1 g of 10% Pd/BaSO₄, and theflask was evacuated and then back-filled with hydrogen (1 atm). Thisprocedure was repeated several times. The reaction was stirred for 12 hand then filtered. The resultant solution was concentrated in vacuo toprovide (±)1-[(1S*,2R*,4R*)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one(quantitative; ˜90% purity). MS found: (M+H)⁺=538.

(28e) To a solution of (±) 1-[(1S*,2R*,4R*)-4-amino-2-(4methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one(0.36 mmol) in dichloroethane (6 mL) was added acetic acid (0.1 mL, 1.8mmol), acetone (0.08 mL, 1.1 mmol), and sodium triacetoxyborohydride(0.23 g, 1.1 mmol). The mixture was heated at 80° C. for 1 h, cooled tort, and quenched with sat. NaHCO₃, and extracted twice with EtOAc. Theorganic extracts were combined, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. A portion of the crude residue waspurified by reverse-phase HPLC to provide two fractions, one of whichcontained the title. MS found: (M+H)⁺=581.

Example 29 (±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one

(29a) The title compound was isolated from a separate fraction of thereverse-phase HPLC purification described in procedure 28e above. MSfound: (M+H)⁺=535.

Example 30 (±)1-[(1S*,2R*,4R*)-4-Isopropylmethylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one

(30a) To a solution of (±)1-[(1S*,2R*,4R*)-4-isopropylamino-2-(4-methylsulfanyl-benzenesulfonyl-methyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one(0.18 mmol) in MeOH (4 mL) was added formaldehyde (0.09 mL of a 37 wt %solution in water, 1.08 mmol) and sodium cyanoborohydride (0.023 g, 0.36mmol). The reaction was stirred for 3 h, quenched with sat. NaHCO₃, andextracted twice with EtOAc. The organic extracts were combined, washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by reverse-phase HPLC to provide the titlecompound. MS found: (M+H)⁺=595.4.

Example 31 (±)1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one

(31a) meta-Trifluoromethoxybenzaldehyde (4.63 g) was incorporated intoprocedure (28a) above to provide 1-(3-trifluoromethoxyphenyl)propenone(2.57 g, 50% yield). A portion of this material (0.35 g, 1.75 mmol) wascarried through procedures (28b)-(28d) to give a residue, which waspurified by reverse-phase HPLC to provide the title compound (0.043 g).MS found: (M+H)⁺=555.2.

Example 32 (±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one

(32a) The product of procedure (31a), (±)1-[(1S*,2R*,4R*)-4-amino-2-(4-methylsulfanyl-benzene-sulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one(0.026 g, 0.046 mmol), was carried through procedure (28e) above toafford the title compound (0.013 g, 47% yield) after purification byreverse-phase HPLC. MS found: (M+H)⁺=597.2.

Example 33 (±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-piperidin-2-one

(33a) The product of procedure (28e), (±)1-[(1S*,2R*,4R*)-4-isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one(˜10 mg), was dissolved in MeOH. The resulting solution was charged with˜20 mg 10% Pd/C, stirred under 1 atm of H₂ for 12 h, filtered, andconcentrated in vacuo. The residue was redissolved in MeOH. Theresulting solution was charged with ˜40 mg 10% Pd/C, stirred under 55atm of H₂ for 12 h, filtered, and concentrated in vacuo. The residue wasredissolved in MeOH. The resulting solution was charged with ˜50 mg 10%Pd/C, stirred under 55 atm of H₂ for 36 h, filtered, and concentrated invacuo. The residue was dissolved in 0.5% TFA/MeCN and concentrated invacuo to afford a mixture of diastereomers as the title compound as itsTFA salt (10 mg). MS found: (M+H)⁺=537.

Example 34(S)-3-(3-(trifluoromethyl)benzylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-(methylthio)phenylsulfonyl)methyl)cyclohexyl)pyrrolidin-2-one

(34a) 3-(Trifluoromethyl)benzaldehyde and sodium cyanoborohydride(instead of 3-trifluoromethylphenyl isocyanate) in MeOH (instead of DMF)were incorporated into Example 18 to give the title compound. MS found:(M+H)⁺=612.3.

Example 353(R′)-(3-(trifluoromethyl)phenethyl)-1-((1S,2R,4R′/S)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(35a) 3-(Trifluoromethyl)phenethyl alcohol (10.0 g, 52.6 mmol),triphenylphosphine (17.9 g, 68.4 mmol), and imidazole (5.00 g, 73.6mmol) were dissolved in acetonitrile (42 mL) and ether (70 mm), then themixture was cooled to 0° C. Iodine (18.7 g, 73.6 mmol) was added inportions, then the mixture was stirred for 4 h. The reaction mixture wasdiluted with ether (1 L), washed with saturated Na₂S₂O₃ (3×300 mm),aqueous CuSO₄ (2×300 mL), and brine (2×300 mL), dried over Na₂SO₄,filtered, and concentrated to a volume of 200 mL. The precipitate oftriphenylphosphineoxide was removed by filtration and the filtrate wastriturated with ether/hexanes (2:1, 300 mL). Additionaltriphenylphosphine-oxide was removed by filtration, and the filtrate wasconcentrated to dryness to provide1-(2-iodoethyl)-3-trifluoromethylbenzene as a yellow oil (16.5 g,quantitative): ¹H NMR (300 MHz, CDCl₃) δ 7.54-7.35 (m, 4H), 3.37 (t,J=8.3 Hz, 2H), 3.24 (t, J=8.3 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ −63.1.

(35b) To a 100-mL three-neck round-bottomed flask equipped with athermometer, addition funnel, and nitrogen inlet was addeddiisopropylamine (2.4 mm, 17.2 mmol) in THF (4 mL). The solution wascooled to −78° C., then a solution of n-BuLi (2.5 M in hexanes, 6.9 mL)was added slowly, followed by HMPA (3.1 mL, 18.0 mmol) and the reactionwas stirred at this temperature for 30 min. A solution ofethylpent-4-enoate (2.0 g, 15.6 mmol) in THF (15.6 mm) was addeddropwise, then the mixture was stirred for 45 min. To this mixture wasadded a solution of 1-(2-iodoethyl)-3-trifluoromethylbenzene (35a) (1.37g, 4.58 mmol) in THF (2 mL) and the resulting mixture was allowed towarm to room temperature overnight. The mixture was diluted with ether(500 mL), washed with water (2×250 mL), and brine (2×250 ml), dried overNa₂SO₄, filtered, and evaporated. The residue was purified by flashchromatography to provide2-[2-(3-trifluoromethylphenyl)ethyl]pent-4-enoic acid ethyl ester (529mg, 39%) as a colorless oil: ESI MS m/z 301 [C₁₆H₁₉F₃O₂+H]⁺.

(35c) 2-[2-(3-Trifluoromethylphenyl)ethyl]pent-4-enoic acid ethyl ester(529 mg, 1.76 mmol) was dissolved in CH₂Cl₂ and cooled to −78° C. Theresulting solution was treated with ozone until a light blue color wasobserved. The solution was degassed with N₂, then polymer-supported Ph₃P(3 mmol/g, 882 mg, 2.64 mmol) was added and the mixture was stirred for3 h at room temperature. The solid was removed by filtration and rinsedwith CH₂Cl₂. Evaporation of the filtrate provided an oil, which waspurified by flash column chromatography (hexanes/ether) to give ethyl2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoateas a colorless oil (151 mg, 25%) and the desired ethyl2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate as a colorless oil(83 mg, 16%). A solution of ethyl2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoate(150 mg, 431 μmol) in CH₂Cl₂ (20 mL) was cooled to −78° C., then Me₂S(0.3 mL, 4.1 mmol) was added and the mixture was stirred for 2 d. Thereaction mixture was diluted with CH₂Cl₂ (300 mL), washed with water(2×100 mL), and brine (100 mm), dried over Na₂SO₄, filtered, andevaporated to provide additional ethyl2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate (123 mg): ¹H NMR(300 MHz CDCl₃) δ 7.50-7.30 (m, 4H), 5.26-5.20 (m, 1H), 5.14 (d, J=1.6Hz, 1H), 5.04 (d, J=6.3 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 2.73-2.57 (m,3H), 2.35-1.77 (m, 4H), 1.29 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃)δ −63.0.

(35d) Ethyl 2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate (83mg, 275 μmol) and(7R,8S)-7-(benzene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine[3g by substitution of phenyl disulfide into step (3d) and skipping step(3f)] (68 mg, 218 μmol) were dissolved in 1,2-dichloroethane (2.3 mL).The resulting solution was stirred at room temperature for 10 min, thensodium triacetoxyborohydride (58 mg, 275 μmol) was added and the mixturewas stirred overnight. The reaction mixture was diluted with CH₂Cl₂ (400mL), washed with saturated NH₄Cl (3×150 mL), and brine (200 mm), driedover Na₂SO₄, filtered and evaporated. The residue was purified by flashcolumn chromatography to give an inseparable mixture of diastereomers4-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-ylamino)-2-[2-(3-trifluoromethylphenyl)ethyl]butyricacid ethyl ester (64 mg, 49%): ESI MS m/z 598 [C₃₀H₃₈F₃NO₆S+H]⁺.

(35e) The mixture of diastereomers from above (35d) (92 mg, 154 mmol)was dissolved in MeOH (10 mL) and NaOMe (85 mg) was added. The mixturewas heated at 50° C. for 16 h, then diluted with EtOAc (300 mL). Themixture was washed with water (3×150 mL) and brine (200 mL), dried overNa₂SO₄, and evaporated in vacuo to dryness. The residue was purified byflash column chromatography to provide(1S,2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(R)-[2-(3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one(upper TLC spot; 30 mg, 35%): ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.80 (m,2H), 7.62-7.35 (m, 7H), 4.03-3.70 (m, 6H), 3.52-3.39 (m, 1H), 3.37-3.25(m, 1H), 3.06 (dd, J=14.6, 2.1 Hz, 1H), 2.88-2.67 (m, 3H), 2.33-1.55 (m,11H); ¹⁹F NMR (282 MHz, CDCl₃) δ −63.0; ESI MS m/z 552[C₂₈H₃₂F₃NO₅S+H]⁺; and (1S,2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(S)-[2-(3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one(lower TLC spot; 34 mg, 41%) ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.80 (m,2H), 7.60-7.35 (m, 7H), 4.03-3.73 (m, 6H), 3.40-3.25 (m, 2H), 2.97 (dd,J=14.3, 1.9 Hz, 1H), 2.80-2.62 (m, 3H), 2.40-1.40 (m, 11H); ¹⁹F NMR (282MHz, CDCl₃) δ −63.0; ESI MS m/z 552 [C₂₈H₃₂F₃NO₅S+H]⁺.

(35f)(1S,2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(R)-[2-(3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one(29 mg, 53 mmol) and p-TsOH (4 mg) in acetone (5 mL) was stirredovernight at room temperature. A second portion of p-TsOH (4 mg) wasadded and the reaction mixture was stirred for an additional 24 h. Thesolvent was evaporated in vacuo and the residue was purified by flashcolumn chromatography to afford(R)-3-(3-(trifluoromethyl)phenethyl)-1-((1S,2R)-4-oxo-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one(17 mg, 64%) as a white solid: ESI MS m/z 508 [C₂₆H₂₈F₃NO₄S+H]⁺.

(35g) To a stirred mixture of the above compound (35f) (17 mg, 34 mmol)and titanium(IV) isopropoxide (0.5 mL, 1.67 mmol) was added2-propylamine (36 mg, 600 mmol). The mixture was stirred at roomtemperature for 3 h, then MeOH (5 mL) was added, followed by NaBH₄ (3.5mg, 94 mmol). After 2 h, the reaction mixture was quenched with 0.5 MNaOH (30 mL) and the resulting mixture was stirred for 2 h. The mixturewas diluted with EtoAc (400 mL), washed with 0.5 M NaOH (3×150 mL) andbrine (200 mL), dried over Na₂SO₄, filtered, and evaporated.Purification of the residue by semi-preparative HPLC gave the titlecompound (10 mg) as a mixture of diastereomers: ¹H NMR (300 MHz, CDCl₃)δ 8.00-7.75 (m, 2H), 7.73-7.30 (m, 7H), 4.60-1.50 (m, 20H), 1.49-1.20(m, 6H).

Example 363(S)-(3-(Trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(36a)(1S,2R)-1-(7-Benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(S)-[2-(3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one(see, 35e) was incorporated into Example 35, step (35f) to give thetitle compound as a mixture of diastereomers. MS found: (M+H)⁺=551.4.

Example 37N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxoazepan-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(37a) To a solution of (S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoicacid (1 g, 6 mmol) in 30 mL of CH₂Cl₂ and 5 mL of MeOH at rt was slowlyadded TMSCHN₂ (10 mL), and the reaction mixture was left with stirringfor 1 h. The solvent was remove under reduced pressure, and theresulting residue was diluted with water and EtOAc. The organic layerwas separated, dried over Na₂SO₄₁ and concentrated to afford an oil(S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid methyl ester. MS[M+H]⁺ 262.

(37b) To a solution of oxalyl chloride (0.33 mL, 0.36 mmol) in CH₂Cl₂(10 mL) at −78 C was added DMSO (0.1 mL, 1.32 mmol). Ten minutes later,a solution of alcohol (S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoicacid methyl ester (144 mg, 0.55 mmol) in CH₂Cl₂ (10 mL) was added andstirred for 15 min before iPr₂NEt (0.5 mL, 2.7 mmol) was added. Thereaction mixture was allowed to warm up to 0 C and left with stirringfor 2 h before water and EtOAc were added. The organic layer wasseparated, dried over Na₂SO₄, and concentrated to afford to a crude oil(S)-2-tert-butoxycarbonylamino-6-oxo-hexanoic acid methyl ester.

(37c) To a solution of(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine (seeexample 10, steps 10a-10d with the substitution of methyl phenyl sulfonein step 10a and then treated with TFA) (135 mg, 0.45 mmol) and(S)-2-tert-butoxycarbonylamino-6-oxo-hexanoic acid methyl ester (140 mg,0.55 mmol) in CH₂Cl₂ (15 mL) at rt was added NaBH(OAc)₃ (194 mg, 0.9mmol). After 16 h, the solution was concentrated. The resulting residuewas re-dissolved in EtOAc and washed with saturated NaHCO₃, water, andbrine. The organic layer was dried, filtered, and concentrated to affordto a crude oil(1S,2R,3S,4R)-6-(4-azido-2-benzenesulfonylmethyl-cyclohexylamino)-2-tert-butoxycarbonylamino-hexanoicacid methyl ester. MS [M+H]⁺=538.

(37d) To a solution of(1S,2R,3S,4R)-6-(4-azido-2-benzenesulfonylmethyl-cyclohexylamino)-2-tert-butoxycarbonylamino-hexanoicacid methyl ester (270 mg) in THF (15 mL) and H₂O (3 mL) at rt was addedLiOH (24 mg). After 1 h, the reaction was diluted with water and EtOAc.Upon adjusting the pH value to 7, the organic layer was collected,dried, and concentrated to afford to a crude oil (140 mg) which wasre-dissolved in DMF (15 mL), followed by the addition of HATU (132 mg,0.34 mmol) and Hunig's base (0.06 mL, 0.34 mmol). The resulting mixturewas stirred for 16 before EtOAc was added. The EtOAc layer was washedwith 1 N HCl, NaHCO₃ solution (aq), and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue gave[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester (120 mg). MS found; (M+H)⁺=506.

(37e) To a solution of[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-carbamicacid tert-butyl ester (120 mg) in CH₂Cl₂ (10 mL) was added TFA (3.3 mL).After 45 min, the solution was diluted with NaHCO₃ solution (aq) andEtOAc. The organic layer was collected, dried, and concentrated toafford to a crude oil3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-azepan-2-one.MS [M+H]⁺=406.

(37f) To a solution of3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-azepan-2-one(50 mg, 0.12 mmol) in DMF (15 mL) was added 3-trifluoromethyl benzoicacid (28 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and Hunig's base (0.03ml, 0.15 mmol). The resulting mixture was stirred for 16 h before EtoAcwas added. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution(aq), and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gaveN-[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-3-trifluoromethyl-benzamide(70 mg). MS found: (M+H)⁺=578.

(37g)N-[(3S)-1-(1S,2R,4R)-(4-Azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-3-trifluoromethyl-benzamide(70 mg) was dissolved in MeOH (10 mL) prior to the addition of 10% Pd/C(20 mg). A hydrogen balloon was added and the solution was stirred at rtfor 16 h. The palladium was filtered and the solvent was concentrated toN-[(3S)-1-(1S,2R,4R)-(4-amino-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-3-trifluoromethyl-benzamide.MS found: (M+H)⁺=552.

(37h) To a solution ofN-[(3S)-1-(1S,2R,4R)-(4-amino-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-3-trifluoromethyl-benzamide(30 mg) in CH₂Cl₂ (15 mL) at rt was added NaBH(OAc)₃ (50 mg), acetone (2mL), and three drops of AcOH. After 2 h, formaldehyde (2 mL) was addedand the solution was stirred for another 2 h. The reaction mixture wasdiluted with EtOAc and washed with saturated NaHCO₃, water, and brine.The organic layer was dried, filtered, and concentrated to afford to acrude oil which was purified by semi-preparative HPLC to give the titlecompound. MS [M+H]⁺=608.

Example 38N—((S)-1-((1S,2R,4R)-4-(dimethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopiperidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(38a) (S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzylester was incorporated into Example 37 (without acetone in step 37h) togive the title compound. MS found: (M+H)⁺=566.

Example 39(R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one

(39a) A mixture of methyl 3-bromopropionate (6a, 10.0 g, 60.0 mmol) andsodium iodide (11.2 g, 74.9 mmol) in acetone (60 mL) was stirred for 30min at room temperature, then heated at reflux for 40 min. The mixturewas cooled in an ice/water bath and the white solid was filtered off,rinsing with acetone. The filtrate was evaporated to dryness to providemethyl 3-iodopropionate (12.3 g, 96%) as a yellow oil: ¹H NMR (300 MHz,CDCl₃) δ 3.73 (s, 3H), 3.33 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H).

(39b) To a 250-mL three-neck round-bottomed flask equipped with athermometer, condenser, and nitrogen inlet was added Zn—Cu couple (3.41g, 52.1 mmol). A solution of methyl 3-iodopropionate (7.27 g, 34.0 mmol)in benzene (67.7 mL) and DMA (4.5 mL) was added over 5 min and themixture was stirred at room temperature for 1 h, then heated at 60° C.for 5 h. A mixture of Pd(PPh₃)₄ (1.05 g, 0.906 mmol) in benzene (22.7mL) was added to the reaction and stirred at 60° C. for 5 min. Themixture was then removed from heat and 3-(trifluoromethyl)benzoylchloride (3.4 mm, 23 mmol) in benzene (11.3 mL) was added immediately.After stirring for 2 h, the mixture was diluted with EtOAc, washed with1 M HCl (3×200 mL), NaHCO₃ (2×200 mL) and brine (1×200 mm), dried overNa₂SO₄, filtered, and evaporated. The crude material was purified byCombiFlash chromatography (silica, 0-70% ether/hexanes) to give4-oxo-4-(3-trifluoromethylphenyl)butyric acid methyl ester (5.35 g, 91%)as an orange oil: ¹H NMR (300 MHz CDCl₃) δ 8.24 (s, 1H), 8.17 (d, J=7.8Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 3.72 (s, 3H),3.35 (t, J=6.5 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃)δ −63.3; ESI MS m/z 261 [C₁₂H₁₁F₃O₃+H]⁺.

(39c) A solution of 4-oxo-4-(3-trifluoromethylphenyl)butyric acid methylester (2.47 g, 9.50 mmol), trimethylorthoformate (4.8 mL), p-TsOH (181mg, 0.95 mmol) and ethylene glycol (7.3 mL) was heated at 50° C. for 3h. The mixture was diluted with EtOAc (500 mL), washed with saturatedNaHCO₃ (3×200 mL), water (2×200 mL), and brine (150 mL), dried overNa₂SO₄, filtered and evaporated to give a mixture of esters. The mixturewas stirred in MeOH (25 mL) with NaOMe (400 mg) at room temperature for6 h. The reaction was quenched with saturated NH₄Cl and the methanol wasremoved by evaporation. The residue was dissolved in EtOAc, washed withsaturated NH₄Cl (2×200 mL), water (2×200 mL) and brine (200 mL), driedover Na₂SO₄, and evaporated to give3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid methylester (2.71 g, 94%) as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.73 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.47 (t,J=7.7 Hz, 1H), 4.10-3.99 (m, 2H), 3.80-3.70 (m, 2H), 3.65 (s, 3H), 2.44(t, J=7.8 Hz, 2H), 2.24 (t, J=7.8 Hz, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ−62.9; ESI MS m/z 305 [C₁₄H₁₅F₃O₄+H]⁺.

(39d) Diisopropylamine (1.74 mL, 12.5 mmol) was dissolved in THF (6.2mL) under a nitrogen atmosphere and cooled to −78° C. A solution ofn-BuLi (2.5 M in hexanes, 5.3 mL) was added dropwise, keeping thetemperature below −67° C. The reaction was warmed to −15° C. for 15 min,then cooled back down to −78° C. A solution of3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid methylester (2.71 g, 8.90 mmol) in THF (1.5 ml) was added and the mixture wasstirred for 40 min. Allyl bromide (0.92 mL, 11 mmol) and HMPA (0.46 mL,2.7 mmol) were added simultaneously and the reaction was stirred at roomtemperature overnight. The mixture was diluted with EtOAc (400 mL),washed with saturated NH₄Cl (3×150 mL), water (2×150 mL), and brine (200mL), dried over Na₂SO₄, filtered, and evaporated. The residue waspurified by CombiFlash chromatography (silica, 0-40% ether/heptane) togive2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]pent-4-enoicacid methyl ester (1.82 g, 59%) as a light yellow oil: ¹H NMR (300 MHz,CDCl₃) δ 7.73 (s, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H),7.46 (t, J=7.7 Hz, 1H), 5.80-5.61 (m, 1H), 5.10-4.97 (m, 2H), 4.10-3.90(m, 2H), 3.80-3.60 (m, 5H), 2.83-2.68 (m, 1H), 2.50-2.13 (m, 3H), 1.97(dd, J=14.7, 2.7 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃) δ −62.9; ESI MS m/z345 [C₁₇H₁₉F₃O₄+H]⁺.

(39e) A solution of2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]pent-4-enoicacid methyl ester (1.82 g, 5.29 mmol) in CH₂Cl₂ (250 mL) was cooled to−78° C. and ozone was bubbled into the solution until a light bluesolution was obtained. The solution was degassed with nitrogen, thendimethylsulfide (4 mL) was added dropwise. The mixture was stirredovernight at room temperature, then heated at reflux for 24 h. Thereaction was diluted with CH₂Cl₂ (500 mL), washed with 1 M HCl (3×150mL) and brine (200 mL), dried over Na₂SO₄, filtered, and evaporated. Theresidue was purified by CombiFlash chromatography (silica, 0-50%ether/hexanes) to give aldehyde4-oxo-2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]butyricacid methyl ester (1.41 g, 77%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃)δ 9.74 (s, 1H), 7.72 (s, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.7 Hz,1H), 7.47 (t, J=7.7 Hz, 1H), 4.12-3.95 (m, 2H), 3.83-3.64 (m, 5H),3.27-3.13 (m, 1H), 2.98-2.70 (m, 2H), 2.40 (dd, J=14.8, 7.2 Hz, 1H),2.04 (dd, J=14.8, 5.5 Hz, 1H); ¹⁹F NMR (282 MHz, CDCl₃) δ −62.9.

(39f) A mixture of(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine (see 37c)(676 mg, 2.30 mmol) and4-oxo-2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]butyricacid methyl ester (794 mg, 2.30 mmol) in 1,2-dichloroethane (46 mL) wasstirred at room temperature overnight. The solvent was removed undervacuum, then the residue was dissolved in MeOH (35 mL) and cooled to 0°C. Sodium borohydride (872 mg, 23.0 mmol) was added in one portion andthe mixture was stirred for 4 h. The reaction was diluted with EtOAc(500 mL), washed with saturated NaHCO₃ (3×150 mL) and brine (200 mL),dried over Na₂SO₄, filtered, and evaporated. The residue was purified byCombiFlash chromatography (silica, 0-100% ether/hexanes) to give amixture of diastereomers methyl4-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-2-((2-(3-(trifluoromethyl)phenyl),3-dioxolan-2-yl)methyl)butanoate (1.04 g, 70%) as a colorless oil: ¹HNMR (300 MHz, CDCl₃) δ 8.00-7.88 (m, 2H), 7.75-7.52 (m, 6H), 7.51-7.41(m, 1H), 4.17-3.88 (m, 2H), 3.80-3.60 (m, 5H), 3.59-3.48 (m, 1H),3.45-3.30 (m, 1H), 3.10-2.98 (m, 1H), 2.85-2.55 (m, 3H), 2.50-2.20 (m,3H), 2.00-1.30 (m, 9H); ¹⁹F NMR (282 MHz, CDCl₃) δ −62.9, −62.8; ESI MSm/z 625 [C₂₉H₃₅F₃N₄O₆S+H]⁺.

(39g) A stirred mixture of diastereomers 39f (1.04 g, 1.66 mmol) andNaOMe (90 mg, 1.66 mg) in MeOH (20 mL) was heated at reflux for 4 d. Thesolvent was removed under vacuum and the residue was dissolved in EtOAc(350 mL). The organic mixture was washed with saturated NH₄Cl (3×100mm), water (200 mL), and brine (200 mL), dried over Na₂SO₄, filtered,and evaporated. The crude material was purified by CombiFlashchromatography followed by preparative TLC to give(S*)-1-((1S*,2R*,4R*)₄-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one(39g-a, 359 mg, 36%) and(R*)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one(39g-b, 322 mg, 33%) as white solids.

For 39g-a: ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.82 (m, 2H), 7.73 (s, 1H),7.70-7.43 (m, 6H), 4.10-3.90 (m, 3H), 3.81-3.57 (m, 3H), 3.55-3.42 (m,1H), 3.40-3.20 (m, 3H), 2.61-2.47 (m, 3H), 2.27-2.10 (m, 2H), 2.00-1.63(m, 7H); ¹⁹F NMR (282 MHz, CDCl₃) δ −62.9; ESI MS m/z 593[C₂₈H₃₁F₃N₄O₅+H]⁺.

For 39g-b: ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.82 (m, 2H), 7.73 (s, 1H),7.69-7.43 (m, 6H), 4.10-3.90 (m, 3H), 3.85-3.57 (m, 3H), 3.44-3.23 (m,3H), 3.22-3.10 (m, 1H), 2.62-1.60 (m, 12H); ¹⁹F NMR (282 MHz, CDCl₃) δ−62.9; ESI MS m/z 593 [C₂₈H₃₁F₃N₄O₅S+H]⁺.

(39h) A mixture of 39g-b (222 mg, 375 μmol) and 10% Pd/C (239 mg, 112μmol) in MeOH (150 mL) was hydrogenated (50 psi) for 2 h. The mixturewas filtered through diatomaceous earth (infusorial earth) and thefiltrate was evaporated under vacuum to give(R*)-1-((1S*,2R*,4R*)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one(39h-b, 169 mg, 80%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.87(d, J=7.3 Hz, 2H), 7.68-7.35 (m, 7H), 4.22 (s, 1H), 4.02-3.60 (m, 5H),3.50-3.14 (m, 4H), 2.80-2.63 (m, 1H), 2.60-1.60 (m, 12H); ¹⁹F NMR (282MHz, CDCl₃) δ −62.8; ESI MS m/z 567 [C₂₈H₃₃F₃N₂O₅S+H]⁺.

(39i) A mixture of 39h-b (170 mg, 300 μmol), acetone (871 μL, 11.9μmol), acetic acid (69.1 μL, 1.20 mmol), and sodiumtriacetoxyborohydride (255 mg, 1.20 mmol) in dichloroethane (17 mL) wasstirred at room temperature for 2 h. The reaction was diluted with EtOAc(500 mL), washed with saturated NaHCO₃ (3×150 mL), water (2×100 mL), andbrine (150 mL), dried over Na₂SO₄, filtered, and evaporated. The residuewas purified by CombiFlash chromatography (silica, 0-10% MeOH/CH₂Cl₂) toprovide(R*)-1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one(39i-b, 106 mg, 58%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.89(d, J=7.2 Hz, 2H), 7.68 (s, 1H), 7.64-7.39 (m, 6H), 4.20 (s, 1H),4.05-3.90 (m, 2H), 3.81-3.60 (m, 3H), 3.48-3.11 (m, 4H), 3.10-2.88 (m,1H), 2.60-2.10 (m, 5H), 2.09-1.60 (m, 8H), 1.43-1.00 (m, 6H); ¹⁹F NMR(282 MHz, CDCl₃) δ −62.9; ESI MS m/z 609 [C₃₁H₃₉F₃N₂O₅S+H]⁺.

(39j) Compound 39i-b (103 mg, 168 μmol) and 37% formaldehyde (50 μL, 1.8mmol) were dissolved in MeOH (2 mL) and stirred for 3 h at roomtemperature. Sodium cyanoborohydride (16 mg, 252 μmol) was added and themixture was stirred for 2 h. The reaction was diluted with EtOAc (400mL), washed with saturated NaHCO₃ (3×150 mL) and brine (100 mL), driedover Na₂SO₄, filtered, and evaporated. The residue was purified byCombiFlash chromatography (silica, 0-10% CH₂Cl₂/MeOH) and thenlyophilized from CH₃CN/H₂O to give title compound (77 mg, 74%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.90-7.82 (m, 2H), 7.71 (s, 1H),7.68-7.42 (m, 6H), 4.15-3.92 (m, 3H), 3.80-3.00 (m, 7H), 2.71-2.10 (m,9H), 1.93-1.40 (m, 9H), 1.17-0.95 (m, 6H); ¹⁹F NMR (282 MHz, CDCl₃) δ−62.9; ESI MS m/z 623 [C₃₂H₄₁F₃N₂O₅S+H]⁺.

Example 40(S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one

(40a) Diastereomer 39g-a was incorporated into Example 39 (steps39h-39j) to give the title compound. MS found: (M+H)⁺=623.

Example 41(S*)-3-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one

(41a) A solution of Example 40 (74.4 mg, 0.120 mmol) in CH₃CN (0.9 mL)and 1 M HCl (0.9 mL) was heated at 60° C. for 5 h. The mixture wasdiluted with ethyl acetate (500 mL), washed with satd NaHCO₃ (3×150 mL)and brine (2×100 mL), dried over Na₂SO₄, filtered, and evaporated todryness. The residue was lyophilized from CH₃CN/H₂O to the titlecompound as a white solid (70.2 mg, >99): ESI MS m/z 579[C₃₀H₃₇F₃N₂O₄S+H]⁺.

Example 42(R*)-3-(2-oxo-2-(3-trifluoromethyl)phenylethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one

(42a) Example 39 was incorporated into Example 41 to give the titlecompound. MS found: (M+H)⁺=579.

Example 43(R*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(43a) To a solution of Example 42 (19.3 mg, 33.4 μmol) in MeOH (2 mL)was added sodium borohydride (6 mg, 167 μmol). After stirring for 1 h,the solvent was removed under vacuum. The residue was dissolved in EtOAc(500 mL), washed with satd NaHCO₃ (3×150 mL) and brine (2×100 mL), driedover Na₂SO₄, filtered, and evaporated to dryness. The residue waspurified by preparative TLC (80:12:6:2 EtOAc/CHCl₃/MeOH/NH₄OH). Themiddle band was lyophilized from CH₃CN/H₂O/TFA to give one diastereomerof the title compound 43a-a (7.9 mg, 34%) as a colorless oil. The bottomband was lyophilized from CH₃CN/H₂O/TFA to give the second diastereomerof the title compound 43a-b (12.1 mg, 66%) as a colorless oil.

For 43a-a: ¹H NMR (300 MHz, CDCl₃) δ 11.13 (br, s, 1H), 8.00-7.89 (m,2H), 7.75-7.40 (m, 7H), 5.06-4.93 (m, 1H), 4.40-4.29 (m, 1H), 4.10-3.03(m, 12H), 3.02-2.90 (m, 1H), 2.89-2.50 (m, 5H), 2.41-2.25 (m, 1H),2.21-1.60 (m, 10H), 1.48-1.40 (m, 3H), 1.38-1.20 (m, 4H); ¹⁹F NMR (282MHz, CDCl₃) δ −62.9, −76.3; ESI MS m/z 581 [C₃₀H₃₉F₃N₂O₄S+H]⁺.

For 43a-b: ¹H NMR (300 MHz, CDCl₃) δ 10.95 (br, s, 1H), 7.98-7.89 (m,2H), 7.76-7.40 (m, 7H), 4.90-4.80 (m, 1H), 4.40-4.30 (m, 1H), 4.10-3.90(m, 1H), 3.89-3.70 (m, 1H), 3.60-3.48 (m, 1H), 3.42-3.02 (m, 2H),3.01-2.90 (m, 1H), 2.89-2.55 (m, 6H), 2.40-2.00 (m, 8H), 1.99-1.55 (m,4H), 1.50-1.40 (m, 3H), 1.37-1.20 (m, 5H); ¹⁹F NMR (282 MHz, CDCl₃) δ−63.0, −76.4; EST MS m/z 581 [C₃₀H₃₉F₃N₂O₄S+H]⁺.

Example 44(S*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(44a) Example 41 was incorporated into Example 43 to give the titlecompound as a mixture of diastereomers. MS found: (M+H)⁺=581.

Example 45((S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(−2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidin-2-onetrifluoroacetate

(45a) A stirred mixture of Example 41 (19.7 mg, 34 μmol),methoxylamine.HCl (17 mg, 204 μmol), NaOAc (17 mg, 204 μmol), and MeOH(2 ml) was heated at 50° C. for 24 h. The solvent was removed undervacuum and the residue was dissolved in EtOAc (500 mL). The organicmixture was washed with satd NaHCO₃ (3×100 mL), water (200 mL), andbrine (200 mL), dried over Na₂SO₄, filtered, and evaporated. The residuewas lyophilized from CH₃CN/H₂O/TFA give the title compound as a mixtureof (E) and (Z) isomers (26.9 mg, 95%): ¹H NMR (500 MHz, CDCl₃) δ 11.03(s, 1H), 7.97-7.86 (m, 3H), 7.83-7.76 (m, 1H), 7.70-7.63 (m, 1H),7.62-7.53 (m, 3H), 7.50-7.41 (m, 1H), 4.32-4.20 (m, 1H), 3.99 (s, 3H),3.95-3.85 (m, 1H), 3.60-3.43 (m, 2H), 3.32-3.20 (m, 1H), 3.15-2.94 (m,2H), 2.91-2.77 (m, 2H), 2.75-2.65 (m, 3H), 2.63-2.50 (m, 2H), 2.20-1.68(m, 7H), 1.50-1.40 (m, 3H), 1.35-1.24 (m, 5H); ¹⁹F NMR (282 MHz, CDCl₃)δ −63.1, −76.3; ESI MS m/z 608 [C₃₁H₄₀F₃N₃O₄S+H]⁺ 0.1.

Example 46((R*)—(1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(−2-(methoxyimino)-2-(3-(trifluoromethyl)-phenyl)ethyl)pyrrolidin-2-onetrifluoroacetate

(46a) Example 42 was incorporated into Example 45 to give the titlecompound as a mixture of (E)/(Z). ¹H NMR (500 MHz, CDCl₃) δ 10.80 (Sr1H), 7.98-7.85 (m, 3H), 7.81-7.40 (m, 6H), 4.40-4.21 (m, 1H), 4.10-3.84(m, 3H), 3.83-3.77 (m, 1H), 3.74-3.58 (m, 1H), 3.50-3.15 (m, 3H),3.14-2.89 (m, 3H), 2.85-2.68 (m, 4H), 2.65-2.49 (m, 2H), 2.20-1.98 (m,5H), 1.93-1.62 (m, 2H), 1.50-1.38 (m, 3H), 1.35-1.20 (m, 5H); ¹⁹F NMR(282 MHz, CDCl₃) δ −63.1, −76.3; ESIMS m/z 608 [C₃₁H₄₀F₃N₃O₄S+H]⁺.

Example 471-((1S*,2R*,4R*)-4-(amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-onetrifluoroacetate

(47a) 3-(Trifluoromethyl)benzene-1,2-diamine (257 mg, 1×46 mmol) wasdissolved in anhydrous DMF (7.5 mL). The mixture was stirred at 0° C.under N₂ as N-methylmorpholine (0.34 mL, 3.09 mmol), compound fromExample 24d (456 mg, 1.12 mmol), andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent, 644 mg, 1.45 mmol) were added sequentially. The mixturewas allowed to warm to room temperature and stirred for 14 h, thendiluted with EtOAc, washed with 10% aqueous HCl (3×), saturated NaHCO₃(1×), and brine (1×), dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by flash column chromatography (silica, 50-100%,EtOAc/hexanes) to provide the two diastereomers ofN-(2-amino-3-(trifluoromethyl)phenyl)-1-((1S*,2R*,4R*)-4-(azido)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidine-3-carboxamideas white crushable foams: ESI MS m/z 565 [C₂₅H₂₇F₃N₆O₄S+H]⁺.

(47b) The diastereomers from above (47a) (136 mg, 0.241 mmol) andp-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) were stirred inanhydrous toluene (35 mL). The reaction vessel was fitted with aDean-Stark trap and the mixture was heated to reflux, at which point 10mL of toluene was removed. The mixture was further heated at reflux for2 h, then allowed to cool to room temperature, and the solvent wasremoved in vacuo. The residue was purified by flash columnchromatography (silica, 2-10% MeOH/CH₂Cl₂) to provide1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneas a mixture of diastereomers (101 mg, 77%); ¹H NMR (300 MHz, CDCl₃) δ10.88-10.77 (m, 1H), 7.94-7.76 (m, 3H), 7.65-7.43 (m, 3H), 7.35-7.23 (m,2H); ESI MS m/z 547 [C₂₅H₂₅F₃N₆O₃S+H]⁺.

(47c) To a solution of the above compound (47b) (154 mg, 0.282 mmol) inmethanol (7 mL) was added 10% Pd/C (wet, 60 mg). The mixture washydrogenated (1 atm) for 14 h, then filtered through a pad ofdiatomaceous earth and concentrated. The residue was purified bypreparative TLC (80:18:2 CHCl₃/MeOH/NH₄OH). After concentrating thematerial in vacuo, the resulting oil was dissolved in CH₃CN/H₂O/TFA andlyophilized to give the title compound (29 mg, 16%) as a white solid andmixture of diastereomers: ESI MS m/z 521 [C₂₅H₂₇F₃N₄O₃S+H]⁺.

Example 481-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-onetrifluoroacetate

(48a) To a solution of Example 47 (67 mg, 0.13 mmol) in1,2-dichloroethane (7.3 mL) was added acetone (0.38 mL, 5.2 mmol) andacetic acid (30 μL, 0.51 mmol). The resulting mixture was stirred for 20min, then sodium triacetoxyborohydride (110 mg, 0.52 mmol) was added.After stirring for 2 h, the mixture was diluted with EtOAc and washedsequentially with saturated aqueous NaHCO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and the solvent wasremoved in vacuo. The resulting clear, glassy solid was dissolved inCH₃CN/H₂O/TFA and lyophilized to provide the title compound (5.1 mg, 6%)as a white solid and mixture of diastereomers: ESI MS m/z 563[C₂₈H₃₃F₃N₄O₃S+H]⁺.

Example 491-((1S*,2R*,4R*)-4-(isopropyl)methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-onetrifluoroacetate

(49a) To a solution of Example 48 (25 mg, 44 μmol) in methanol (1.5 mL)was added a solution of 37% aqueous formaldehyde (14 mL, 178 μmol). Theresulting mixture was stirred for 2 h, then sodium cyanoborohydride (5mg, 67 μmol) was added. After stirring for 3 h, the mixture was treatedwith saturated aqueous NaHCO₃ and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered, and thesolvent removed in vacuo. The residue was purified by preparative TLC(90:10:1 CHCl₃/MeOH/NH₄OH). After concentrating the material in vacuo,the resulting oil was dissolved in CH₃CN/H₂O/TFA and lyophilized to givethe title compound (10 mg, 33%) as a white solid and mixture ofdiastereomers: ESI MS m/z 577 [C₂₉H₃₅F₃N₄O₃S+H]⁺.

Example 501-((1S*,2R*,4R*)-4-(isopropyl(ethyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-onetrifluoroacetate

(50a) To a solution of Example 48 (25 mg, 44 μmol) in 1,2-dichloroethane(3.0 mL) was added acetaldehyde (13 μL, 222 μmol) and acetic acid (30μL, 0.14 mmol). The resulting mixture was stirred for 20 min, thensodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. Afterstirring for 2 h, the mixture was diluted with EtOAc and washedsequentially with saturated aqueous NaHCO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and the solvent wasremoved in vacuo. The residue was purified by preparative TLC (70:30CH2Cl2/MeOH). After concentrating the material in vacuo, the resultingoil was dissolved in CH₃CN/H₂O/TFA and lyophilized to provide the titlecompound (10 mg, 34%) as a white solid and mixture of diastereomers: ESIMS m/z 591 [C₃₀H₃₇F₃N₄O₃S+H]⁺.

Example 511-((1S*,2R*,4R*)-4-(Diethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-onetrifluoroacetate

(51a) To a solution of Example 47 (25 mg, 44 μmol) in 1,2-dichloroethane(2.7 mL) was added acetaldehyde (28 μL, 492 μmol) and acetic acid (8 μL,96 μmol). The resulting mixture was stirred for 20 main, then sodiumtriacetoxyborohydride (31 mg, 144 μmol) was added. After stirring for 2h, the mixture was diluted with EtOAc and washed sequentially withsaturated aqueous NaHCO₃, water, and brine. The organic phase was driedover Na₂SO₄, filtered, and the solvent was removed in vacuo. The residuewas purified by preparative TLC (90:10:1 CHCl₃/MeOH/NH₄OH). Afterconcentrating the material in vacuo, the resulting oil was dissolved inCH₃CN/H₂O/TFA and lyophilized to provide the title compound (8.5 mg,26%) as a white solid and mixture of diastereomers: ESI MS m/z 577[C₂₉H₃₅F₃N₄O₃S+H]⁺.

Example 521-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(naphthalen-1-ylamino)pyrrolidin-2-onetrifluoroacetate

(52a) (1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylaminetrifluoroacetate (see 37c) (2.5 g, 6.3 mmol) was dissolved in DMF (15mL) prior to the addition of BOP reagent (3.4 g) and N-Boc-L-Met-OH (1.9g). After cooling to 0° C., NMM (2.6 mL) was added. The resultingmixture was warmed to rt and was stirred overnight. The solution wasdiluted with EtOAc, and was washed successively with brine and sat.NaHCO₃. The organic phase was dried (MgSO₄), filtered, and concentrated.Flash chromatography of the resulting residue gave tert-butyl(S)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate(2.8 g) as a mixture of diastereomers. MS found: (M+H)⁺=526.2.

(52b) The above derivative (52a) was dissolved in MeI (30 mL). Afterstirring overnight at rt, the solution was concentrated and dried. Theresulting material was dissolved in DMF (30 mL) prior to the addition ofCs₂CO₃ (3.5 g). After stirring 3 h, the solution was diluted with EtOAcand was washed with brine. The organic phase was dried (MgSO₄),filtered, and concentrated. Flash chromatography (1:2 up to 2:1EtOAc/hexane) of the resulting residue provided the bottom diastereomertert-butyl(S)-1-((1S,2R,4R)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate(600 mg). MS found: (M+H)⁺=478.3.

(52c) A portion of the above material (52b) (30 mg) was dissolved inMeOH (4 mL) prior to the addition of 10% Pd/C (20 mg). A hydrogenballoon was added and the mixture was stirred. After stirring 2 h, thePd/C was filtered off and the solvent was concentrated to givetert-butyl(S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate(29 mg). MS found: (M+H)⁺=452.2.

(52d) The above material (52c) was dissolved in dichloroethane (5 mL)prior to the addition of glacial acetic acid (0.2 mm), acetone (1.0 mL),and NaBH(OAc)₃ (20 mg). After 20 h, MeOH (4 mL) was added prior to theaddition of 37% formaldehyde in water (1 mL). After 15 min, NaBH₃CN (20mg) was added. After 1 h, saturated NaHCO₃ was added and some of theMeOH was removed. EtOAc was added and the organic layer was dried,filtered, and concentrated to give tert-butyl(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate(15 mg). MS found: (M+H)⁺=508.3.

(52e) A portion of above material (52b) (160 mg) was dissolved in CH₂Cl₂(3 mL) and cooled to 0° C. prior to the addition of TFA (4 mL). Afterthe reaction was warmed to rt over 1 h, it was concentrated. Thismaterial was dissolved in EtOAc (8 mL) prior to the addition ofsaturated Na₂CO₃ solution (3 mL). The organic phase was dried (Na₂CO₃),filtered, and concentrated to afford free base(S)-3-amino-1-((1S,2R,4R)-4(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one(130 mg). MS found: (M+H)⁺=408.2.

(52f) A portion of the above material (52e) (30 mg, 74 μmol), sodiumtert-butoxide (14 mg, 140 μmol), and toluene (0.7 mL) were placed in areaction tube equipped with a stir bar and screw cap. After passingargon through the reaction mixture for 2 min, BINAP (8 mg, 13 μmol),Pd₂(dba)₃ (4 mg, 4 μmol) and 1-bromonaphthalene (9 μL, 61 μmol) wereadded sequentially. The mixture was evacuated again with argon, thensealed and heated to 85° C. overnight. After cooling to roomtemperature, the mixture was diluted with ether, filtered through a padof diatomaceous earth, and concentrated. The residue was purified bysemi-preparative HPLC, then lyophilized to provide the title compound(9.5 mg) as a gray solid and mixture of diastereomers. ESI MS m/z 534[C₃₁H₃₉N₃O₃S+H]⁺.

Example 533-(Benzo[b]thiophen-3-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(53a) A portion of the above amine (52e) (27 mg, 66 μmol), sodiumtert-butoxide (13 mg, 130 μmol), and toluene (0.7 mL) were placed in areaction tube equipped with a stir bar and screw cap. After passingargon through the reaction mixture for 2 min,2-(di-t-butylphosphino)biphenyl (12 mg, 40 μmol), Pd₂(dba)₃ (6 mg, 7μmol) and 3-bromothianaphthene (18 μL, 130 μmol) were addedsequentially. The mixture was evacuated again with argon, then sealedand stirred overnight. The mixture was diluted with ether, filteredthrough a pad of diatomaceous earth, and concentrated. The residue waspurified by preparative TLC (9:1 CH₂Cl₂/MeOH), then lyophilized toprovide the title compound (4.4 mg) as a light yellow solid and mixtureof diastereomers. ESI MS m/z 540 [C₂₉H₃₇N₃O₃S₂+H]⁺.

Example 54(S)-3-(6-chloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexylpyrrolidin-2-one trifluoroacetate

(54a) The above amine (52e) (20 mg), triethylamine (0.03 mL), and4,6-dichloroquinazoline (15 mg) were dissolved in EtOH (2 mL) and placedin a microwave. The reaction was heated at 100° C. for 22 min. Thesolution was filtered and the filtrate was subjected to reverse phaseHPLC purification (gradient elution, water/acetonitrile/TFA) to providethe title compound (11.3 mg). MS found: (M+H)⁺=570.2.

Example 55(S)-3-(6,8-dichloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(55a) 4,6,8-Trichloroquinazoline was incorporated into Example 54 togive the title compound. MS found: (M+H)⁺=604.2.

Example 563,5-Dichloro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamidetrifluoroacetate

(56a) Amine 52e (15 mg) was dissolved in DMF (2 mL) prior to theaddition of diisopropylethylamine (0.02 mL) and 3,5-dichlorobenzoic acid(10 mg). After cooling to 0° C., BOP reagent (19 mg) was added. Theresulting mixture was warmed to rt and was stirred overnight. Thesolution was diluted with EtOAc and was washed with sat. NaHCO₃. Theorganic phase was dried (MgSO₄), filtered, and concentrated. Reversephase HPLC purification (gradient elution, water/acetonitrile/TFA) ofthe resulting residue provided the title compound (1.0 mg). MS found:(M+H)⁺=580.

Example 57N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamidetrifluoroacetate

(57a) 3-Trifluoromethoxybenzoic acid was incorporated into Example 56 togive the title compound. MS found: (M+H)⁺=596.2.

Example 58 3-((E)-3(R*)-(trifluoromethylstyryl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(58a) Compound 39g-b (2.0 g) was dissolved in CH₃CN (25 mL) and 1 M HCl(25 mL) was stirred at 60° C. for 6 h. The mixture was diluted withethyl acetate (500 mL), washed with satd NaHCO₃ (3×150 mL) and brine(2×100 mL), dried over Na₂SO₄, filtered, and evaporated to dryness togive1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*)-(3-(trifluoromethyl)benzoyl)pyrrolidin-2-oneas a white solid (1.85 g). ESI MS m/z 549 [C₂₆H₂₇F₃N₄O₄S+H]⁺.

(58b) A solution of LiHMDS (5.06 mL, 1 M in hexanes) in THF (50.6 mL)was cooled to −78° C. A precooled solution of compound (58a) (2.80 g,5.06 mmol) in THF (25 mL) was added dropwise. The mixture was stirredfor 1 h at −78° C. then a precooled solution of2-[(N,N-bistrifluoromethylsulfonyl)amino]-5-chloropyridine (2.90 g, 7.38mmol) in THF (30 mL) was added. After 90 min, the reaction was warmed to−5° C. and stirred for 2 h. The mixture was diluted with EtOAc (800 mL),washed with satd NH₄Cl (3×150 mL) and brine (100 mL), dried over Na₂SO₄,filtered, and concentrated, filtering off the 2-amino-5-chloropyridinebyproduct. The filtrate was evaporated to dryness, and purified by flashchromatography (silica-gel, 0-100% EtOAc/hexanes) to give2-(1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-1-(3(R*)-(trifluoromethyl)phenyl)vinyltrifluoromethanesulfonate (2.30 g, 67%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 7.92-7.83 (m, 2H), 7.78-7.50 (m, 7H), 6.07 (d, J=9.0 Hz,1H), 4.00-3.89 (m, 5H), 3.22 (dd, J=14.7, 3.4 Hz, 1H), 2.80-2.45 (m,2H), 2.18-1.60 (m, 9H); ¹⁹F NMR (282 MHz, CDCl₃) δ −63.4 (3F), −74.1(3F).

(58c) A mixture of Pd(PPh₃)₄ (25.5 mg, 22 μmol) and LiCl (140 mg, 3.29mmol) in THF (3.28 mL) was stirred under argon atmosphere. A solution ofcompound 58b (750 mg, 1.03 mmol) in THF (3.68 mL) was added, followed byslow addition of tributyltin hydride (μL, 1.32 mmol). The mixture wasstirred 4 h at room temperature, diluted with EtOAc (500 mL), washedwith satd NaHCO₃ (3×100 mL), brine (200 mL), dried over Na₂SO₄,filtered, and evaporated. The residue was purified by flashchromatography (silica gel with a plug of RF, 0-80% EtOAc/hexanes) togive the3(R*)-((E)-3-(trifluoromethyl)styryl)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one(347 mg, 59%) as white solids. ESI MS m/z 533 [C₂₆H₂₇F₃N₄O₃S+H]⁺.

(58d) A mixture of 58c (117 mg, 220 μmol) and triphenylphosphine (115mg, 440 μmol) in THF (10 mL) was stirred at room temperature for 23 h.Water (2 mL) was added and the mixture was stirred for 2 d. The volumewas reduced under vacuum and the residue was dissolved in EtOAc (500nm). The mixture was extracted with 1 M HCl (3×150 mL), and the aqueouslayer was made basic with 6 N NaOH, then extracted with EtOAc (3×150mL). The organic layer was dried over Na₂SO₄, filtered, and evaporatedto give crude free amine. This material (24 mg, 47 μmol), acetone (200μL, 2.73 mmol), and acetic acid (20 μL, 348 μmol) in 1,2-dichloroethane(4 mL) was stirred for 3 min, then treated with sodiumtriacetoxyborohydride (20 mg, 95 μmol). After stirring the mixture for 1h, the solvent was removed under vacuum. The residue was dissolved inMeOH (4 mL), then 37% aqueous formaldehyde (400 μL) and sodiumcyanoborohydride (4.5 mg, 71 μmol) were added. The mixture was stirred18 h, and the solvent was removed under vacuum. The residue was purifiedby semi-preparative HPLC, and the product lyophilized from CH₃CN/H₂O/TFAto give the title compound (23.8 mg). ESI MS m/z 563 [C₃₀H₃₇F₃N₂O₃S+H]⁺.

Example 591-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2-onetrifluoroacetate

(59a) A suspension of copper bromide-dimethylsulfide (1.03 g, 5.01 mmol)in THF (10 mL) was cooled to −78° C. Methylmagnesium bromide (3 M inether, 3.34 mL, 10 mmol) was added dropwise, then the mixture wasremoved from the dry ice bath and THF (3 mL) was added. After stirringfor 7 min, the mixture was cooled to −78° C. A solution of compound 58b(569 mg) in THF (11 mL) was added dropwise and the reaction mixture wasstirred for 2 h. The mixture was diluted with EtOAc (500 mL), washedwith satd NH₄Cl (3×100 mL) and brine (200 mL), dried over Na₂SO₄,filtered, and evaporated. The residue was purified by flash columnchromatography (silica-gel, 0-70%, THF/hexanes) to provide1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2-one(436 mg). ESI MS m/z 547 [C₂₇H₂₉F₃N₄O₃S+H]⁺.

(59b) The above material 59a was incorporated into Example 58 (step 58d)to give the title compound. MS found: (M+H)⁺=577.

Example 60N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)benzamidedetrifluoroacetate

(60a) Benzoic acid was incorporated into Example 56 to give the titlecompound. MS found: (M+H)⁺=512.

Example 61N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamidetrifluoroacetate

(61a) (1S,2R)-cis-2-Methoxycarbonyl-cyclohex-4-ene-1-carboxylic acid(66.0 g, see Bolm et al. J. Org. Chem. 2000, 65, 6984-6991) wasdissolved in dry acetone (815 mL) prior to the addition of triethylamine(43.4 g). This solution was cooled to 0° C. and ethyl chloroformate(46.7 g) was added. The resulting solution was stirred 1 h before NaN₃(35.0 g) was added. The cooling bath was removed, and the reaction waswarmed to rt overnight. All solid material was removed by filtration,and the solution was partially concentrated. Water was slowly added andthe organic layer was separated. The aqueous layer was extracted withether. The combined organic layers were washed with water and brinebefore they were dried, filtered, and concentrated. The resulting oil(66.1 g) was dissolved in benzene (800 mL) and was warmed to a gentlereflux. After 4 h, the solution was cooled back to rt. Benzyl alcohol(37.5 g) and p-TsOH (1.5 g) were added, and the solution was warmed backto a gentle reflux overnight. After cooling to rt, the reaction waswashed with NaHCO₃ and brine, dried, filtered, and concentrated to give(1R,8S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methylester (97.7 g). MS found: (M+H)⁺=290.2.

(61b) A sample of(1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methylester (91.4 g) was dissolved in MeOH (500 mL) prior to the dropwiseaddition of NaOH (25.3 g) in water (95 mL). After 3 h, the solution waspartially concentrated and an Et₂O/water mixture was added. The aqueouslayer was separated and was acidified (pH ˜2) with concentrated HCl. Theresulting mixture was extracted with EtOAc. The combined organic layerswere washed with water and brine before they were dried, filtered, andconcentrated to give(1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g).MS found: (M+H)⁺=276.2.

(61c) A sample of(1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72 g)was dissolved in CH₂Cl₂ (750 mL) prior to the addition of CDI (50.9 g).After 2.5 h water was added, and the solution was extracted with CH₂Cl₂.The combined organic layers were dried, filtered, and concentrated. Theresulting material was dissolved in CH₂Cl₂ and ammonia gas was bubbledthrough the solution for 1.5 h. After stirring overnight, the majorityof the solvent was removed and Et₂O was added. The product precipitatedas a white solid and was collected to give(1R,6S)-6-carbamoylcyclohex-3-enyl)carbamic acid benzyl ester (61.5 g).MS found: (M+H)⁺=275.3.

(61d) A sample of (1R,6S)-6-carbamoylcyclohex-3-enyl)-carbamic acidbenzyl ester (30.7 g) was dissolved in THF (1100 mL) and NMP (220 mL).At −78° C., 2.3M n-BuLi (96.3 mL) was added dropwise. After 2 h, asolution of Boc₂O (24.4 g) in THF (40 mL) was added dropwise. Thissolution was stirred 1.2 h before it was quenched with a saturated NH₄CLsolution. Water and Et₂O were added. The organic layer was filtered thenwashed with water, brine, dried, filtered, and concentrated. Flashchromatography of the resulting residue gave(1R,6S)-(6-tert-butoxycarbonylaminocarbonyl-cyclohex-3-enyl)-carbamicacid benzyl ester (29.2 g). MS found: (M+Na)⁺=397.4.

(61e) A sample of(1R,6S)-(6-tert-butoxycarbonyl-aminocarbonylcyclohex-3-enyl)carbamicacid benzyl ester (29.0 g) was dissolved in THF (1290 mL). This wascooled in an ice/brine bath prior to the addition of n-BuLi (1.5 mL,2.4M). After 30 min, iodine (59.0 g) was added in a single portion. Thebath was removed, and the reaction was warmed to rt overnight. Theresulting solution was quenched with saturated thiosulfate solution.Water and EtOAc were added. The organic layer was washed with water,brine, dried, filtered, and concentrated. The resulting slurry wasdiluted with Et₂O and(1R,2S,4S,5R)-2-benzyloxycarbonyl-amino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester (22.8 g) was collected by vacuum filtration. MSfound: (M−C₅H₈O₂+H)⁺=401.1.

(61f) A sample of(1R,2S,4S,5R)-2-benzyloxycarbonylamino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester (43.3 g) was dissolved in benzene (580 mL) priorto the addition of Bu₃SnH (27.8 g) and AIBN (0.7 g). The resultingmixture was warmed to a gentle reflux for 3 h. After cooling, thesolvent was removed and hexane was added. The resulting white solid wascollected by vacuum filtration to give (1R,2S,SR)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester (29.5 g). MS found: (M+Na)⁺=397.4.

(61g) A solution of(1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester (10.21 g, 27.3 mmol) in tetrahydrofuran (200 mL)was treated with water (40 mL) and then with sodium borohydride (5.16 g,136 mmol). The mixture was stirred at room temperature for 2 h, then wastreated with saturated aqueous sodium bicarbonate and stirred until thebubbling subsided. The mixture was extracted three times with ethylacetate. The combined extracts were washed with saturated aqueous sodiumchloride, dried over sodium sulfate, and concentrated under vacuum. Theresidue was recrystallized from ethyl acetate-hexane to provide(1R,3R,4S)-(4-benzyloxy carbonylamino-3-hydroxymethylcyclohexyl)carbamicacid tert-butyl ester as a white solid (6.8 g); additional product (2.1g) was obtained by flash column chromatography of the residue fromconcentration of the mother liquors, eluting with 40%, then 50% ethylacetate-hexane. MS found: (M+H)⁺=379.28.

(61h) A solution of(1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamicacid tert-butyl ester (3.49 g, 9.22 mmol) in tetrahydrofuran (40 mL) wastreated with diphenyl disulfide (4.03 g, 18.4 mmol) andtri-n-butylphosphine (4.6 mL, 18.4 mmol) and the solution was heated atreflux for 17 h. The mixture was cooled and concentrated under vacuum,and the residue was purified by flash column chromatography, elutingwith 10%, then 20% ethyl acetate-hexane, to provide(1S,2R,4R)-(4-tert-butoxycarbonylamino-2-phenyl-sulfanylmethylcyclohexyl)-carbamicacid benzyl ester (4.37 g) as a white glassy solid. MS found:(M+H)⁺=471.65.

(61i) A solution of(1S,2R,4R)-(4-tert-butoxycarbonyl-amino-2-phenylsulfanylmethylcyclohexyl)carbamicacid benzyl ester (4.37 g, 9.22 mmol) in 2-propanol (100 mL) was treatedwith a solution of Oxone (11.34 g, 18.44 mmol) in water (60 mL). Themixture was stirred at room temperature for 18 h, then was diluted withwater and extracted with ethyl acetate. The organic phases were washedwith water, then with brine, then were dried over sodium sulfate andconcentrated under vacuum to provide(1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl)-carbamicacid benzyl ester (4.77 g) as a white glassy solid, used without furtherpurification. MS found: (M+H)⁺=503.6.

(61j) A mixture of(1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl)carbamicacid benzyl ester (2.96 g, 5.9 mmol) and 20% palladium hydroxide oncharcoal (Pearlman's catalyst, 2.0 g) in methanol (100 mL) was stirredunder one atmosphere of hydrogen at room temperature for 16.5 h. Themixture was filtered through Celite, and the solids were washed withmethanol. The filtrate was concentrated under vacuum and the residue wasdissolved in dichloromethane. The solution was dried over sodium sulfateand concentrated under vacuum to provide(1R,3R,4S)-(4-amino-3-benzenesulfonylmethylcyclohexyl)-carbamic acidtert-butyl ester (2.02 g) as a white glassy solid, used without furtherpurification. MS found: (M+H)⁺=369.62.

(61k) This material (61j) was incorporated into Steps 52a to 52b(substituting N-Cbz-L-Met-OH for N-Boc-L-Met-OH) to give tert-butyl(1R,3R,4S)-4-((S)-2-oxo-3-(2-phenylacetamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate.MS found: (M+H)⁺=586.6.

(61l) A portion of above material (61k) (2.0 g) was dissolved in CH₂Cl₂(5 mL) and cooled to 0° C. prior to the addition of TFA (7 mL). Afterthe reaction was warmed to rt over 1 h, it was concentrated and dried.This material, acetone (993 mg), and acetic acid (1 mL) in1,2-dichloroethane (15 mL) was stirred for 3 min, then treated withsodium triacetoxyborohydride (1.4 g). After stirring for 20 h, MeOH (10mL) was added followed by 37% aqueous formaldehyde (2 mL) and sodiumcyanoborohydride (427 mg) were added. The mixture was stirred 3 h, andthe solvent was removed under vacuum. The residue was dissolved in EtOAc(200 min), washed with saturated NaHCO₃, dried over Mg₂SO₄, filtered,and evaporated to provideN—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-2-phenylacetamide(2.7 g). MS found: (M+H)⁺=542.2.

(61m) A portion of above material (61l) (300 mg) was dissolved in 33%(wt) HBr/AcOH (3 mL). After 30 min, Et₂O (20 mL) was added and a whitesolid precipitated from solution. This solid was collected to give(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onedihydrogen bromide (300 mg). MS found. (M+H)⁺=408.2.

(61n) The above material (61m) was dissolved in EtOAc (8 mL) prior tothe addition of saturated Na₂CO₃ solution (3 mL). The organic phase wasdried (Na₂CO₃), filtered, and concentrated to afford free base(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one(210 mg). MS found: (M+H)⁺=408.2.

(61o) A portion of the above material (61n) (30 mg) was dissolved in DMF(1 mL) prior to the addition of NMM (29.3 mg) and3,5-ditrifluoromethylbenzoic acid (16.2 mg). After cooling to 0° C., BOPreagent (38 mg) was added. The resulting mixture was warmed to rt andwas stirred overnight. The solution was diluted with EtOAc and waswashed with sat. NaHCO₃. The organic phase was dried (MgSO₄), filtered,and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (X.0 mg). MS found: (M+H)⁺=648.

Example 622-Amino-N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)-5-(trifluoromethoxy)benzamidetrifluoroacetate

(62a) 2-(tert-Butoxycarbonylamino)-5-(trifluoromethoxy)benzoic acid wasincorporated into Step (61o) to give the tert-butyl2-((1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarbamate.MS found: (M+H)⁺=711.

(62b) The above material (62a) (20 mg) was dissolved in CH₂Cl₂ (2 mL)and cooled to 0° C. prior to the addition of TFA (4 mL). After thereaction was warmed to rt over 30 min, it was concentrated and dried toprovide the title compound. MS found: (M+H)⁺=611.

Example 63(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-onetrifluoroacetate

(63a) Compound (61n) (30 mg), sodium tert-butoxide (10.1 mg),4-chloro-6-trifluoromethylquinoline (25 mg), and toluene (1.3 mL) wereplaced in a reaction vial equipped with a stir bar and screw cap. Afterpassing argon through the reaction mixture for 2 min, acetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (1 mg) wasadded and the solution was heated to 80° C. overnight. After cooling toroom temperature, the mixture was concentrated and then dissolved inMeOH before it was filtered. The filtrate was purified by reverse phaseHPLC purification (gradient elution, water/acetonitrile/TFA) to providetwo diastereomers. The first diastereomer off the HPLC being the titlecompound (10.0 mg). MS found: (M+H)⁺=603.2.

Example 64(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-onetrifluoroacetate

(64a) The second diastereomer off the HPLC from Example 63 is the titlecompound. MS found: (M+H)⁺=603.2.

Example 65(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-onetrifluoroacetate

(65a) 4-Chloro-7-trifluoromethylquinoline was incorporated into Example63 to give the title compound as the first diastereomer. MS found:(M+H)⁺=603.2.

Example 66(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-onetrifluoroacetate

(66a) The second diastereomer off the HPLC from Example 65 is the titlecompound. MS found: (M+H)⁺=603.2.

Example 673-(2-(Phenyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(67a) 2-Bromo-biphenyl was incorporated into Example 63 to give thetitle compound as a mixture of diastereomers. MS found: (M+H)⁺=560.3.

Example 683-(3,5-Bis(trifluoromethyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate

(68a) 3,5-Ditrifluoromethyl-1-bromobenzene was incorporated into Example63 to give the title compound as a mixture of diastereomers. MS found:(M+H)⁺=620.2.

Example 691-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(2-(trifluoromethyl)phenylamino)pyrrolidin-2-onetrifluoroacetate

(69a) 2-Trifluoromethyl-1-bromobenzene was incorporated into Example 63to give the title compound as a mixture of diastereomers. MS found:(M+H)⁺=552.3.

Example 701-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(2-methoxyphenylamino)pyrrolidin-2-onetrifluoroacetate

(70a) 2-Methoxy-1-bromobenzene was incorporated into Example 63 to givethe title compound as a mixture of diastereomers. MS found:(M+H)⁺=568.3.

Example 711-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(3-(trifluoromethyl)phenylamino)pyrrolidin-2-onetrifluoroacetate

(71a) 3-Trifluoromethyl-1-bromobenzene was incorporated into Example 63to give the title compound as a mixture of diastereomers. MS found:(M+H)⁺=552.3.

Example 721-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(4-(trifluoromethyl)phenylamino)pyrrolidin-2-onetrifluoroacetate

(72a) 4-Trifluoromethyl-1-bromobenzene was incorporated into Example 63to give the title compound as a mixture of diastereomers. MS found:(M+H)⁺=552.3.

Example 733-Chloro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamidetrifluoroacetate

(73a) 3-Chlorobenzoic acid was incorporated into Step (61o) to give thetitle compound. MS found: (M+H)⁺=546.

Example 743-Fluoro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethyl)benzamidetrifluoroacetate

(74a) 3-Fluoro-5-trifluoromethylbenzoic acid was incorporated into Step(61o) to give the title compound. MS found: (M+H)⁺=598.

Example 75 tert-Butyl(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate

(75a) Compound (61k) (1.0 g) was dissolved in MeOH (15 mL) prior to theaddition 10% Pd/C (200 mg). A hydrogen balloon was attached and thesolution was stirred 18 h. The mixture was filtered through Celite, andthe solids were washed with methanol. The filtrate was concentrated toprovide tert-butyl(1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate(980 mg) as a white glassy solid, used without further purification. MSfound: (M+H)⁺=452.2.

(75b) The above material (75a, 980 mg) was dissolved in DMF prior to theaddition of 4-methylmorpholine (NMM) (481.5 mg) and3-trifluoromethyl-benzoic acid (581.7 mg). After cooling to 0° C., BOPreagent (1.4 g) was added. The resulting mixture was warmed to rt andwas stirred overnight. EtOAc was added along with saturated NaHCO₃solution. The EtOAc layer was washed with NaHCO₃ solution (aq), dried(MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue provided the title compound (978 mg). MS found:(M+H)⁺=624.7.

Example 76N—((S)-2-Oxo-1-((1S,2R,4R)-4-(phenylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(76a) Example 75 (970 mg) was dissolved in CH₂Cl₂ (2 mL) and cooled to0° C. prior to the addition of TFA (7 mL). After the reaction was warmedto rt over 1 h, it was concentrated and dried to provideN—((S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate (1.01 g). MS found: (M+H)⁺=524.1.

(76b) The above material (76b) was dissolved in EtOAc (10 mL) prior tothe addition of saturated Na₂CO₃ solution (4 mL). The organic phase wasdried (Na₂CO₃), filtered, and concentrated to afford free baseN—((S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide(850 mg). MS found: (M+H)⁺=524.1.

(76c) A portion of compound (76b) (10 mg), sodium tert-butoxide (3.5mg), bromobenzene (0.1 mL), and toluene (1.0 mL) were placed in areaction vial equipped with a stir bar and screw cap. After passingargon through the reaction mixture for 2 min, [Pd(μ-Br) (t-Bu₃P)]₂ (1mg) was added and the solution was heated to 80° C. overnight. Aftercooling to room temperature, the mixture was concentrated and thendissolved in MeOH before it was filtered. The filtrate was purified byreverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) to provide the title compound (4.5 mg). MSfound: (M+H)⁺=600.1.

Example 77N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyridin-4-ylamino)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(77a) Sodium-tert-butoxide (11 mg, 0.114 mmol), 3-bromopyridine (14 mg,0.086 mmol), and precatalyst acetato(2-di-t-butylphosphino-1,1-biphenyl-2-yl)palladium(II) (2 mg, 0.004mmol) were added to compound (76b) (30 mg) in toluene (2 mL), degassedby bubbling argon for 30 min. The vial was sealed under argon and thereaction heated overnight at 90° C. Brine (1 mL) was added to quench thereaction and the mixture was evaporated to dryness in vacuo. The cruderesidue was taken up in acetonitrile/water (1:1, 2.5 mL) and purified byC18 HPLC (acetonitrile/water 0.05% TFA) to give the title compound (6.7mg) as a mixture of diastereomers. ESI MS m/z 601 [C₃₀H₃₁F₃N₄O₄S+H]⁺.

Example 78N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(thiazol-2-ylamino)cyclohexylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(78a) 2-Bromothiazole was incorporated into Example 77 to give the titlecompound as a mixture of diastereomers. MS found: (M+H)⁺=607.

Example 79 Methyl(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate

(79a) Compound 76a (20 mg) was dissolved in THF (4 mL) prior to theaddition of saturated NaHCO₃ solution (0.5 mL) and methyl chloroformate(0.5 mL). After 3 h, EtOAc was added along with saturated NaHCO₃solution. The EtoAc layer was washed with NaHCO₃ solution (aq), dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) of the resulting residueprovided the title compound (9.3 mg). MS found: (M+H)⁺=582.2.

Example 80N—((S)-1-((1S,2R,4R)-4-Formamido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide

(80a) Compound 76a (30 mg) was dissolved in DMF prior to the addition of4-methylmorpholine (NMM) (481.5 mg) and concentrated formic acid (0.1mL). After cooling to 0° C., EDC (20 mg) was added. The resultingmixture was warmed to rt and was stirred overnight. EtOAc was addedalong with saturated NaHCO₃ solution. The EtOAc layer was washed withNaHCO₃ solution (aq), dried (MgSO₄), filtered, and concentrated. Reversephase HPLC purification (gradient elution, water/acetonitrile/TFA) ofthe resulting residue provided the title compound (9.1 mg). MS found:(M+H)⁺=552.3.

Example 811-((1R,3R,4S)-4-((S)-2-Oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea

(81a) Compound 76a (77 mg) was dissolved in CH₂Cl₂ (2 mL) at 0° C. priorto the addition of 2,6-lutidine (51 mg) and phenyl chloroformate (38mg). After 1 h at rt, CH₂Cl₂ was added along with saturated NaHCO₃solution. The organic layer was washed with NaHCO₃ solution (aq), dried(MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue provided phenyl(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate(43.7 mg). MS found: (M+H)⁺=644.3.

(81b) A portion of the above compound (81a) (20 mg) was dissolved inDMSO (1 mL) prior to the addition of concentrated ammonium hydroxidesolution (0.5 mL). After 1 h, the mixture was filtered. The filtrate waspurified by reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) to provide the title compound (4.9 mg). MSfound: (M+H)⁺=567.3.

Example 821-Methyl-3-((1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea

(82a) 2.0 M Methylamine in THF was incorporated into Example 81 to givethe title compound. MS found: (M+H)⁺=581.3.

Example 83N—((S)-2-oxo-1-((1S,2R,4R)-4-(2-oxopyrrolidin-1-yl)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide

(83a) 4-Chlorobutyrylchloride (27 mg, 0.191 mmol) was added dropwise tocompound 76b (50 mg) and triethylamine (97 mg, 0.722 mmol) in CH₂Cl₂ (2mL) at room temperature under nitrogen. After 1 h the reaction wasdiluted with ethyl acetate (12 mL) then washed with water (1×5 mL), 10%citric acid (1×5 mL), sat'd NaHCO₃ (1×5 mL), and brine (1×5 mL), driedover MgSO₄, and evaporated to dryness. The residue was purified by flashchromatography (silica gel, 80% ethyl acetate/hexanes to 10%methanol/ethyl acetate) to provideN—((S)-1-((1S,2R,4R)-4-(4-chlorobutanamido)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideas a clear film (40 mg). ESI MS m/z 628 [C₂₉H₃₃ClF₃N₃O₅S+H]⁺.

(83b) The above compound (83a) (40 mg) in THF (1 mL) was added to sodiumhydride (60% in mineral oil, 5 mg, 0.128 mmol) in THF (2 mL) at roomtemperature under nitrogen. After 3 h the reaction was quenched withsat'd NH₄Cl (5 mL) and extracted with ethyl acetate (3×5 mL). Thecombined organic extracts were washed with brine (1×5 mL), dried overMgSO₄, then evaporated to dryness. The residue was purified using C18HPLC (acetonitrile/water 0.05% TFA) to give the title compound (21.7 mg)as a white powder after lyophilization. ESI MS m/z 592[C₂₉H₃₂F₃N₃O₅S+H]⁺.

Example 84N—((S)-1-((1S,2R,4R)-4-(1,1-dioxido-isothiazolidin-2-yl)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide

(84a) 3-Chloropropanesulfonylchloride was incorporated into Example 83(in place of 4-chlorobutyrylchloride) to give the title compound. MSfound: (M+H)⁺=628.

Example 85N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamidetrifluoroacetate

(85a) A portion of compound (61g) (500 mg) and 10% Pd/C (112 mg) in MeOH(150 mL) was hydrogenated at 40 psi on a Paar shaker for 4 h. Themixture was filtered through diatomaceous earth, rinsed with MeOH, thenevaporated to dryness to give tert-butyl(1R,3R,4S)-4-amino-3-(hydroxymethyl)cyclohexylcarbamate as a colorlessoil (348 mg). ESI MS m/z 245 [C₁₂H₂₄N₂O₃+H]⁺.

(85b) To a portion of the above (85a) (4.14 g) in CH₂Cl₂ (169 mL) wasadded sodium bicarbonate (1.53 g), followed by dropwise addition ofTrocCl (2.48 mL). The mixture was stirred at room temperature overnight,then diluted with CH₂Cl₂ (800 mL), washed with satd NaHCO₃ (3×150 mL)and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to(1S,2R,4R)-(4-tert-butoxycarbonylamino-2-hydroxymethylcyclohexyl)carbamicacid 2,2,2-trichloroethyl ester (7.14 g) as a white solid. ESI MS m/z319 [C₁₅H₂₅Cl₃N₂O₅-Boc+H]⁺.

(85c) A mixture of 85b (7.14 g), bis(p-chlorophenyl)disulfide (9.76 g,34 mmol), and tri-n-butylphosphine (26 mL, 187 mmol) in THF (426 mL) wasstirred under a nitrogen atmosphere at 75° C. for 16 h. The solvent wasremoved under vacuum, the residue was diluted with MeCN (800 mL), washedwith hexanes (4×200 mL), concentrated, and flash chromatography(silica-gel, 0-50% ether/hexanes) afforded(1R,3R,4S)-[3-(4-chlorophenylsulfanylmethyl)-4-(2,2,2-trichloroethoxycarbonylamino)-cyclohexyl]carbamicacid tert-butyl ester (6.73 g) as a white solid: ¹H NMR (300 MHz, CDCl₃)δ 7.30-7.18 (m, 4H), 5.06 (d, J=99.2 Hz, 1H), 4.78 (d, J=12.1 Hz, 1H),4.69 (d, J=12.1 Hz, 1H), 4.46 (d, J=7.5 Hz, 1H), 4.20-4.09 (m, 1H), 3.42(br s, 1H), 2.94 (dd, J=13.4, 7.2 Hz, 1H), 2.69 (dd, J=13.4, 7.2 Hz,1H), 2.22-2.08 (m, 1H), 2.05-1.78 (m, 3H), 1.68-1.38 (m, 10H), 1.34-0.82(m, 2H).

(85d) A solution of 85c (6.73 g) in CH₂Cl₂ (41 mL) was cooled to 0° C.;3-chloroperoxy-benzoic acid (70%, 6.38 g, 25.8 mmol) was addedportion-wise. The mixture was stirred for 4 h, then diluted with CH₂Cl₂(800 mL), washed with satd NaHCO₃ (3×150 mL) and brine (100 mL), driedover Na₂SO₄, filtered, and concentrated to give(1R,3R,4S)-[3-(4-chlorobenzenesulfonylmethyl)-4-(2,2,2-trichloroethoxycarbonylamino)cyclohexyl]carbamic acid tert-butyl ester (7.13 g) as an off-whitesolid. ESI MS m/z 478 [C₂₁H₂₈Cl₄N₂O₆S-Boc+H]⁺.

(85e) To a solution of 85d (1.00 g) in THF (16 mL) was added glacialacetic acid (33 mL), followed by activated zinc dust (3.00 g). Themixture was stirred for 8 h, then diluted with EtOAc (500 mL), washedwith satd Na₂CO₃ (3×150 mL) and brine (100 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by CombiFlashchromatography (silica-gel, MeOH/CH₂Cl₂) to give tert-butyl(1R,3R,4S)-4-amino-3-((4-chlorophenylsulfonyl)methyl)cyclohexylcarbamate(561 mg) as yellow solid. ESI MS m/z 403 [C₁₈H₂₇ClN₂O₄S+H]⁺.

(85f) To a solution of 85e (561 mg) and N-Cbz-L-methionine (591 mg) inDMF (9.3 mL), cooled to 0° C., was added N-methylmorpholine (458 μL) andBOP reagent (925 mg). The mixture was stirred overnight at roomtemperature, then diluted with EtOAc (500 mL), washed with satd NaHCO₃(3×150 mL), NH₄Cl (3×150 mL), 5% aqueous LiCl (3×150 mL), and brine (100mL), dried over Na₂SO₄, filtered, and concentrated to give crude(1R,3R,4S)-[4-(2-benzyloxycarbonylamino-4-methylsulfanylbutyrylamino)-3-(4-chlorobenzenesulfonylmethyl)cyclohexyl]carbamicacid tert-butyl ester (953 mg) as a yellow solid. ESI MS m/z 668[C₃₁H₄₂ClN₃O₇S₂+H]⁺.

(85g) A mixture of 85f (6.42 g, 9.60 mmol) and iodomethane (70 mL) wasstirred overnight at room temperature. Methylene chloride (200 mL) wasadded and the iodomethane was azeotroped off under vacuum, repeating 6-8times. The residue was dissolved in CH₂Cl₂ (200 mL), concentrated to ¼volume under vacuum, and the resultant white solid was filtered (2.47 g,sulfonium salt by-product). The filtrate was concentrated to provide ayellow solid (6.80 g), which was used without further purification. Thisyellow solid (6.80 g), cesium carbonate (5.47 g, 16.8 mmol), and DMF(129 mL) was stirred 6 h at room temperature. More cesium carbonate(5.47 g, 16.8 mmol) was added and the reaction was stirred overnight.The mixture was diluted with EtOAc (1 L), washed with water (3×600 mL),5% aqueous LiCl (3×600 mL), and brine (450 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography (silica-gel, 50-100% EtOAc/hexanes) to give(1S,2R,4R)-{1-[4-tert-butoxycarbonylamino-2-(4-chlorobenzenesulfonylmethyl)cyclohexyl]-2-oxo-pyrrolidin-3-yl}carbamicacid benzyl ester (3.21 g) as white solid. ESI MS m/z 620[C₃₀H₃₈Cl₁N₃O₇S+H]⁺.

(85h) Compound 85g was incorporated into step 62b to give benzyl(S)-1-((1S,2R,4R)-4-amino-2-((4-chlorophenylsulfonyl)methyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate:¹H NMR (300 MHz, CDCl₃) δ 10.46 (br, s, 3H), 7.90-7.60 (m, 4H),7.55-7.42 (m, 2H), 7.40-7.29 (m, 3H), 5.65 (d, J=7.3 Hz, 1H), 4.88 (s,2H), 4.34-4.09 (m, 2H), 3.86-3.64 (m, 1H), 3.60-3.20 (m, 4H), 2.77-2.30(m, 3H), 2.20-1.70 (m, 6H).

(85i) A mixture of 85h (875 mg, 1.38 mmol), acetone (3.03 mL, 41.4mmol), and acetic acid (159 μL, 2.76 mmol) in 1,2-dichloroethane (30 mL)was stirred for 3 min, then treated with sodium triacetoxyborohydride(585 mg, 2.76 mmol). After stirring the mixture for 3 h, more acetone (4mL), acetic acid (0.4 mL), and sodium triacetoxyborohydride (300 mg,1.42 mmol) were added. After stirring the reaction mixture overnight,the solvent was removed under vacuum. The residue was dissolved in MeOH(30 mL); 37% aqueous formaldehyde (6 mL) and sodium cyanoborohydride(130 mg, 2.07 mmol) were added. The mixture was stirred 8 h. The solventwas removed under vacuum; the residue was taken up in CH₂Cl₂ (300 mL),washed with satd NaHCO₃ (3×100 mL) and brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under vacuum to afford benzyl(S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate(707 mg) as a yellow solid. ESI MS m/z 576 [C₂₉H₃₈ClN₃O₅S+H]⁺.

(85j) A mixture of 85i (536 mg) and 33% HBr in HOAc (15 mL) was stirred30 minutes at room temperature. The mixture was triturated with ether(3×50 mL) and the residue was dissolved in MeOH (50 mL). The solvent wasevaporated under vacuum to provide(S)-3-amino-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-onedihydrogen bromide (436 mg) as a tan solid, which was used withoutfurther purification in the next step. ESI MS m/z 442[C₂₁H₃₂ClN₃O₃S+H]⁺.

(85k) To a solution of crude 85j (92 mg) and3-fluoro-5-(trifluoromethyl)benzoic acid (48 mg) in DMF (1.01 mL),cooled to 0° C., was added N-methylmorpholine (50 μL) and BOP reagent(101 mg). The mixture was stirred overnight at room temperature, dilutedwith EtOAc (500 mL), washed with satd NaHCO₃ (3×150 mL), NH₄Cl (3×150mL), 5% aqueous LiCl (3×150 mL), and brine (100 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by semi-preparativeHPLC to give the title compound (71.2 mg) as a .TFA salt afterlyophilization from MeCN/H₂O. ESI MS m/z 632 [C₂₉H₃₄ClF₄N₃O₄S+H]⁺.

Example 863-Chloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamidetrifluoroacetate

(86a) 3-Chlorobenzoic acid was incorporated into Example 85 (step 85k)to give the title compound. MS found; (M+H)⁺=580.

Example 87N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamidetrifluoroacetate

(87a) 3,5-Bis(trifluoromethyl)benzoic acid was incorporated into Example85 (step 85k) to give the title compound. MS found: (M+H)⁺=683.

Example 88 tert-Butyl2-(((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarbamate

(88a) 2-tert-Butoxycarbonylamino-5-trifluoromethoxybenzoic acid wasincorporated into Example 85 (step 85k) to give the title compound. MSfound: (M+H)⁺=746.

Example 892-Amino-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamidetrifluoroacetate

(89a) Example 88 was incorporated into Example 62 (step 62b) to give thetitle compound. MS found: (M+H)⁺=645.

Example 90N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamidetrifluoroacetate

(90a) 3-Trifluoromethoxybenzoic acid was incorporated into Example 85(step 85k) to give the title compound. MS found: (M+H)⁺=630.2.

Example 91N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(91a) 3-Trifluoromethylbenzoic acid was incorporated into Example 85(step 85k) to give the title compound. MS found: (M+H)⁺=614.0.

Example 923,5-Dichloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamidetrifluoroacetate

(92a) 3,5-Dichlorobenzoic acid was incorporated into Example 85 (step85k) to give the title compound. MS found: (M+H)⁺=614.2.

Example 933-Chloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamideN-Oxide

(93a) A solution of Example 86 (13.6 mg) in CH₂Cl₂ (1.5 mL) was cooledto 0° C., then 3-chloroperoxybenzoic acid (77%, 10 mg) was addedportion-wise. The mixture was stirred for 1.25 h, then diluted withCH₂Cl₂ (400 mL), washed with sand NaHCO₃ (3×100 mL) and brine (100 mL),dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby semi-preparative HPLC to give the title compound (6.8 mg, 57%) as awhite solid after lyophilization from MeCN/aqueous TEA. ESI MS m/z 596[C₂₈H₃₅Cl₂N₃O₅S+H]⁺.

Example 94N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideN-Oxide

(94a) Example 91 was incorporated into Example 93 to give the titlecompound. MS found: (M+H)⁺=630.3.

Example 95N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamideN-Oxide

(95a) Example 85 was incorporated into Example 93 to give the titlecompound. MS found. (M+H)⁺=649.1.

Example 96N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideN-Oxide

(96a) Example 5 was incorporated into Example 93 to give the titlecompound. MS found: (M+H)⁺=596.3.

Example 97N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-isopropylphenylsulfonyl)methyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideTrifluoroacetate

(97a) The compound from step 61f (4.0 g) was dissolved in MeOH (30 mL)prior to the addition of 10% Pd/C (600 mg). A hydrogen balloon was addedand the mixture was stirred for 3 h. The Pd/C was filtered off and thesolvent was concentrated to give (1R,2S,5R)-tert-butyl2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g). MSfound: (M+H)⁺=241.1

(97b) This material (97a) was incorporated into Steps 52a to 52b(substituting N-Cbz-L-Met-OH for N-Boc-L-Met-OH) to give(1R,2S,5R)-tert-butyl2-((S)-3-(benzyloxycarbonyl)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate.MS found: (M+H)⁺=458.3.

(97c) A mixture of 97b (1.20 g) and 10% Pd/C (558 mg) in MeOH (200 mL)was hydrogenated at 1 atm for 4 h. The mixture was filtered throughdiatomaceous earth with MeOH wash and evaporated to dryness to give(1R,2S,5R)-tert-butyl2-((S)-3-amino-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate(779 mg) as a yellow solid that was used without further purification inthe next step: ¹H NMR (300 MHz, CDCl₃) δ 4.40-4.15 (m, 2H), 3.68 (t,J=99.0 Hz, 1H), 3.53-3.40 (m, 2H), 3.28-3.12 (m, 1H), 2.70-2.60 (m, 1H),2.46-2.10 (m, 6H), 1.96-1.60 (m, 5H), 1.54 (s, 9H).

(97d) To a mixture of 97c (779 mg), 3-(trifluoromethyl)benzoic acid (687mg), and DMF (12 mL), cooled to 0° C., was added N-methylmorpholine (793μL, 7.23 mmol) and BOP reagent (1.60 g, 3.61 mmol). The mixture wasstirred overnight at room temperature, diluted with EtOAc (800 mL),washed with satd NaHCO₃ (3×150 mL), NH₄Cl (3×150 mL), 5% aqueous LiCl(3×150 mL), and brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-15% MeOH/CH₂Cl₂) to give (1R,2S,5R)-tert-butyl7-oxo-2-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-6-aza-bicyclo[3.2.1]octane-6-carboxylate(1.20 g) as white solid. ESI MS m/z 496 [C₂₄H₂₈F₃N₃O₅S+H]⁺.

(97e) To a solution of 97d (1.20 g, 2.42 mmol) in THF (18.6 mL) andwater (3.6 mL) was added sodium borohydride (460 mg, 12.1 mmol) portionwise. After stirring the mixture for three hours, satd NaHCO₃ (50 mL)was added and the mixture was stirred for an additional 15 min. Themixture was diluted with ethyl acetate (500 mL), washed with satd NaHCO₃(3×150 mL) and brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated to give tert-butyl(1R,3R,4S)-3-(hydroxymethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate(1.12 g) as a white solid. ESI MS m/z 500 [C₂₄H₃₂F₃N₃O₅+H]⁺.

(97f) A mixture of 97e (100 mg),bis(p-1,2-bis(4-isopropylphenyl)disulfane (121 mg), andtri-n-butylphosphine (0.3 mL) in THF (5 mL) was stirred under a nitrogenatmosphere at 75° C. for 16 h. The solvent was removed under vacuum, theresidue was diluted with MeCN (500 mL), washed with hexanes (4×200 mL),concentrated, and preparative TLC afforded tert-butyl(1R,3R,4S)-3-((4-isopropylphenylthio)methyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate(79.7 mg) as a mixture of isomers. ESI MS m/z 634 [C₂₄H₃₂F₃N₃O₅+H]⁺.

(97g) The compound from above (97f) was incorporated into Step 3e togive tert-butyl(1R,3R,4S)-3-((4-isopropylphenylsulfonyl)methyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate:¹H NMR (300 MHz, CDCl₃) δ 8.10-7.76 (m, 4H), 7.75-7.62 (m, 1H),7.61-7.30 (m, 3H), 4.90-4.04 (m, 2H), 3.87-3.20 (m, 4H), 3.13-2.86 (m,1H), 2.80-2.42 (m, 1H), 2.36-1.50 (m, 25H), 0.99-0.75 (m, 4H); ¹⁹F NMR(282 MHz, CDCl₃) δ −63.1, −63.2.

(97h) The compound from above (97g) was incorporated into Step 611 togive the title compound after HPLC. MS found: (M+H)⁺=622.3.

Example 98N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(o-tolylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(98a) 1,2-diortho-tolyldisulfane was incorporated into Example 97 fromStep 97f to 97h to give the title compound. MS found: (M+H)⁺=594.6.

Example 99N—((S)-1-((1S,2R,4R)-2-((4-Fluorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamidetrifluoroacetate

(99a) 1,2-bis(4-Fluorophenyl)disulfane was incorporated into Example 97from Step 97f to 97h to give the title compound. MS found: (M+H)⁺=598.5.

Example 1003-Chloro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamidetrifluoroacetate

(100a) Compound 97b was incorporated into Step 97e to give(1S,2R,4R)-(1-[4-tert-butoxycarbonylamino-2-(hydroxymethyl)cyclohexyl]-2-oxo-pyrrolidin-3-yl)carbamicacid benzyl ester. MS found: (M+H)⁺=462.

(100b) Compound 100a was incorporated into Step 97f (with1,2-dipara-tolyldisulfane instead ofbis(p-1,2-bis(4-isopropylphenyl)disulfane) and then Step 97g to give(1S,2R,4R)-{1-[4-tert-butoxycarbonylamino-2-(4-methylbenzenesulfonylmethyl)cyclohexyl]-2-oxo-pyrrolidin-3-yl}carbamicacid benzyl ester. MS found: (M+H)⁺=600.

(100c) Compound 100b was taken into Steps 85h-85j to give(S)-3-amino-1-((1S,2R,4R)-2-((4-methylphenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-onedihydrogen bromide. MS found: (M+H)⁺=584.

(100d) Compound 100c was taken into Step 85k (with 3-chlorobenzoic acidinstead 3-fluoro-5-trifluoromethyl-benzoic acid) to give the titlecompound. MS found: (M+H)⁺=560.2.

Example 1012-Amino-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamidemidetrifluoroacetate

(101a) 2-(tert-Butoxycarbonyl)-5-(trifluoromethyl)benzoic acid wasincorporated into Step (100d) to give tert-butyl2-(((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarbamate.MS found: (M+H)⁺=725.

(101b) The above material (101a) (20 mg) was dissolved in CH₂Cl₂ (2 mL)and cooled to 0° C. prior to the addition of TFA (4 mL). After thereaction was warmed to rt over 30 min, it was concentrated and dried toprovide the title compound. MS found: (M+H)⁺=625.2.

Example 1021-[(1S,2R,4R)-(4-Amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluoromethylphenyl]-5,6-dihydro-1H-pyridin-2-one

(102a) A solution of compound 61j (1.45 g, 3.9 mmol) in methanol (10 mL)was stirred on an ice bath and treated dropwise over 40 min with asolution of 1-(3-trifluoromethylphenyl)propenone (see procedure 28a, 786mg, 3.9 mmol). The mixture was stirred at room temperature for 2 h, thenwas concentrated under vacuum. The residue was purified by flash columnchromatography, eluting with 55% ethyl acetate-hexane, to provide(1R,3R,4S)-{3-benzene-sulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-propylamino]cyclohexyl}carbamicacid tert-butyl ester (1.16 g) as a white glassy solid. MS found:(M+H)⁺=569.35.

(102b) A suspension of sodium hydride (60%, 176 mg, 4.4 mmol) intetrahydrofuran (5 mL) was stirred on an ice bath and treated dropwiseover 5 min with dimethylphosphonoacetic acid tert-butyl ester (0.79 mL,4.0 mmol). The mixture was stirred at room temperature for 25 min, thenwas cooled on an ice bath and treated with a solution of(1R,3R,4S)-{3-benzenesulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-propylamino]cyclohexyl}carbamicacid tert-butyl ester (1.138 g, 2.0 mmol) in tetrahydrofuran (5 mL). Themixture was stirred at room temperature for 2.5 h, then was treated withsaturated aqueous ammonium chloride. The mixture was extracted withethyl acetate, and the organic extracts were dried over sodium sulfateand concentrated under vacuum. The residue was purified by flash columnchromatography, eluting with 25% ethyl acetate-hexane, to provide the Eisomer of5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonyl-aminocyclohexylamino)-3-(3-trifluoromethylphenyl)pent-2-enoicacid tert-butyl ester (511 mg) as a white solid. MS found:(M+H)⁺=667.41. Further elution with 40% ethyl acetate-hexane providedthe corresponding Z isomer (567 mg) as a white glassy solid. MS found:(M+H)⁺=667.41.

(102c) A solution of the E isomer of5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl-amino)-3-(3-trifluoromethylphenyl)pent-2-enoicacid tert-butyl ester (495 mg) in dichloromethane (10 mL) was treatedwith trifluoroacetic acid (5 mL). After standing at room temperature for4 h, the mixture was concentrated under vacuum to provide the E isomerof5-([1S,2R,4R]-4-amino-2-benzenesulfonylmethylcyclohexylamino)-3-(3-trifluoromethyl-phenyl)pent-2-enoicacid, bis-trifluoroacetic acid salt, as a white glassy solid (736 mg)containing excess trifluoro-acetic acid. MS found: (M+H)⁺=511.20.Without further purification, this material was dissolved indichloromethane (5 mL) and 20, treated sequentially withdiisopropylethylamine (0.78 mL, 4.45 mmol),4-(N,N-dimethylamino)pyridine (91 mg, 0.74 mmol) and TBTU (262 mg, 0.82mmol). The solution was stirred at room temperature for 17.5 h, then wasdiluted with dichloromethane, washed with saturated aqueous sodiumbicarbonate, dried over sodium sulfate and concentrated under vacuum.The residue was purified by flash column chromatography, eluting with 4%methanol-dichloromethane containing 0.4% aqueous ammonia, and then byreverse phase HPLC. The resulting product was converted to the free baseby partitioning between 1N sodium hydroxide and ethyl acetate to providethe title product (130 mg) as a white glassy foam. MS found:(M+H)⁺=493.37.

Example 1031-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one

(103a) A solution of1-[(1S,2R,4R)-(4-amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluoromethylphenyl)]-5,6-dihydro-1H-pyridin-2-one(120 mg, 0.243 mmol) in 1,2-dichloroethane (2.5 mL) was treatedsequentially with acetone (0.054 mL, 0.071 mmol), acetic acid (0.07 mL,1.22 mmol) and sodium triacetoxyborohydride (155 mg, 0.731 mmol). Themixture was stirred at room temperature for 3 h, then was concentratedunder vacuum. The residue was partitioned between saturated aqueoussodium bicarbonate and ethyl acetate, and the organic extracts weredried over sodium sulfate and concentrated under vacuum to provide thetitle product (110 mg) as a white glassy solid. MS found: (M+H)⁺=535.21.

Example 1041-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one

(104a) A solution of1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one(41 mg, 0.077 mmol) in methanol (1 mL) was treated with aqueousformaldehyde (37%, 0.029 mL, 0.383 mmol) and the mixture was stirred for45 min. Sodium cyanoborohydride (7 mg, 0.115 mmol) was added, and themixture stirred at room temperature for 2 h. Water was added and themixture was extracted with ethyl acetate. The extracts were washed withbrine, dried over sodium sulfate and concentrated under vacuum toprovide the title product (42 mg) as a white glassy solid. MS found:(M+H)⁺=548.67.

Example 1051-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one

(105a) Following the procedure of Example 104 but substitutingacetaldehyde for aqueous formaldehyde,1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one(43 mg, 0.08 mmol) was converted to the title product (45 mg) as a whiteglassy solid. MS found: (M+H)⁺=563.29.

Example 1061-[1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt Part A. Preparation of6-Chloro-2-trifluoromethyl-quinazolin-4-ol

2-Amino-5-chlorobenzamide (Avocado) (1.00 g, 5.86 mmol, 1.0 eq.) andethyl trifluoroacetate (4.19 mL, 35.2 mmol, 6.0 eq.) were dissolved in50 mL of ethanol at rt under nitrogen and followed by the addition of3.09 M sodium ethoxide in ethanol (11.38 mL, 35.2 mmol, 6.0 eq.) Themixture was refluxed 20 hours. Cooled to rt. Added 10 mL of 10%HOAc/H2O, Solids formed which were filtered, rinsed with 5 mL H2O, thendissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo to give1.35 g of amber solids. LCMS detects (M+H)+=249.

Part B. Preparation of 4,6-Dichloro-2-trifluoromethyl quinazoline

6-Chloro-2-trifluoromethyl-quinazolin-4-ol (1.35 g, 5.43 mmol, 1 eq.),phosphorous oxychloride (4.88 mL, 52.4 mmol, 9.64 eq.) and triethylamine(2.43 mL, 17.4 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3×from methylene chloride then dissolved in methylene chloride and rinsed3× with saturated sodium bicarbonate, 1× with brine. Dried and strippedin vacuo to give an amber oil. Purified over silica gel in 9:1Hexanes/EtOAc. Obtained 800 mg of off-white solids as product. Theproduct was used immediately in Example 1 Part C.

Part C

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(40 mg, 0.0982 mmol, 1 eq., see compound 52e),4,6-dichloro-2-trifluoromethyl-quinazoline (239 mg, 0.105 mmol, 1 eq.)and triethylamine (55 ul, 0.419, 4 eq.) were dissolved in 3 mL ofethanol then microwaved at 100° C. until reaction was complete by LCMS.Purified by LCMS. Obtained 17 mg of product. LCMS detects (M+H)+=638.

Example 1071-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt Part A. Preparation of 7-Chloro-quinazolin-4-ol

2-Amino-4-chloro-benzoic acid (1.00 g, 11.7 mmol, 1.0 eq.), formamidineacetate (3.64 mL, 35.0 mmol, 3 eq.), and ethoxyethanol (20 mL) wererefluxed under nitrogen overnight. Cooled to rt. Added 25 mL of diethylether. Solids precipitated. Filtered off solids. Pumped under highvacuum to give 2.75 g of white solids as product. LCMS detects(M+H)+=181.

Part B. Preparation of 4,7-Dichloro-quinazoline

7-Chloro-quinazolin-4-ol (1.1 g, 6.09 mmol, 1 eq.), phosphorousoxychloride (5.47 mL, 58.7 mmol, 9.00 eq.) and triethylamine (2.73 mL,19.6 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped then restripped3× from methylene chloride, then dissolved in methylene chloride andrinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried andstripped in vacuo to give an amber oil, Purified over silica gel in 9:1to 3:1 Hexanes/EtOAc. Obtained 1.00 g of tan solids as product. LCMSdetects (M+H)+=199.

107. Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106c starting from(3S*)-3-amino-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4,7-dichloro-quinazoline. LCMS detects (M+H)+=570.

Example 108 Part A Preparation of 6-Chloro-quinazoline-2,4-diol

2-Amino-5-chlorobenzamide (Avocado) (3.00 g, 17.5 mmol, 1.0 eq.) wassuspended in 105 mL of H₂O and 1.75 mL of HOAc at rt. A 12 mL solutionof H₂O and sodium cyanate (2.80 g, 43.0 mmol, 2.46 eq.) was then addedslowly. Stirred at 35° C. for 1 hour. Added 31.26 mL of 1.0 N NaOHslowly. Solids precipitated. Cooled to 0° C. Carefully added conc. HClto pH=3. Filtered solids. Solids were then stirred in diethyl ether thenrefiltered and pumped under high vacuum to give 3.36 grams of tan solidsas product. LCMS detects (M+H)+=197.

Part B. Preparation of 2,4,6-Trichloro-quinazoline

6-Chloro-quinazoline-2,4-diol (0.50 g, 2.54 mmol, 1 eq.), phosphorousoxychloride (2.14 mL, 22.9 mmol, 9 eq.) and 2,6-lutidine (0.44 mL, 3.82mmol, 1.5 eq.) were refluxed under nitrogen for 2 hours. The reactionwas stripped then restripped 3× from methylene chloride, then dissolvedin methylene chloride and rinsed 3× with saturated sodium bicarbonate,1× with brine. Dried and stripped in vacuo to give an amber oil.Purified over silica gel in 9:1 to 3:1 Hexanes/EtOAc. Obtained 0.22 g oflight colored solids as product. ¹H NMR (400 MHz) (CD₃OD) δ 8.36 (s,1H), 8.09 (d, 1H, J=7 Hz), 7.97 (d, 1H, J=7 Hz).

Example 108 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(75 mg, 0.184 mmol, 1 eq.), 2,4,6-trichloro-quinazoline (43 mg, 0.184mmol, 1 eq.) N,N-diisopropylethylamine (64 mL, 0.368 mmol, 2 eq.) in THF(3 mL) were refluxed overnight. Purified by HPLC. Obtained 62 mg ofwhite solids. LCMS detects (M+H)+=604.

Example 109 Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-dimethylamino-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S*)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one(27 mg, 0.0375 mmol, 1 eq.), 2.0 M dimethylamine in THF (0.94 ml, 1.88mmol, 50 eq.), and THF (1 mL) were refluxed until reaction was completeby LCMS. Purified by HPLC. Obtained 22 mg of white solids as product.LCMS detects (M+H)+=613.

Example 110 Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-hydroxy-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one(20 mg) and dimethyl sulfoxide (2 mL) were heated at 60° C. undernitrogen until reaction was complete by LCMS. Purified by HPLC to give6.0 mg of white solids as product. LCMS detects (M+H)+=586.

Example 111 Part A. Preparation of 6-Trifluoromethyl-quinazolin-4-ol

2-Amino-5-trifluoromethyl-benzamide (ButtPark) (1.00 g, 4.90 mmol, 1eq.) and formic acid (3.30 mL, 87.2 mmol, 17.8 eq.) were refluxed for2.5 hours. Cooled to rt then added water (10 mL). Stirred 15 minutesthen filtered off solids which were present. The solids were dried at110° C. for 3 hours to give 520 mg of white solids as product. LCMSdetects (M+H)+=215.

Part B. Preparation of 4-Chloro-6-trifluoromethyl-quinazoline

6-Trifluoromethyl-quinazolin-4-ol (0.95 g, 4.44 mol, 1 eq.), phosphorousoxychloride (2.48 mL, 26.6 mmol, 6 eq.) and triethylamine (3.71 mL, 26.6mmol, 6 eq.) were refluxed for 2.5 hours. Stripped 3× from methylenechloride then dissolved in methylene chloride and rinsed 3× withsaturated NaHCO3, 1× with brine. Dried and stripped in vacuo to give andamber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 560mg of off-white solids as product. The product was used immediately inEx 111 part C.

Example 111 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4-Chloro-6-trifluoromethyl-quinazoline. Purified by HPLC. Obtained57 mg of white solids as title product. LCMS detects (M+H)+=604.

Example 112 Part A. Preparation of6-tert-Butyl-thieno[3,2-d]pyrimidin-4-ol

3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.00 g,4.69 mmol, 1 eq.), formamidine acetate (1.46 g, 4.69 mmol, 3 eq.) and2-ethoxyethanol (10 mL) were refluxed under nitrogen for 4 hours.Purified over silica gel in 3:1 to 1:1 Hexanes/ethyl acetate to 100%ethyl acetate to obtain 970 mg of yellow solids as product. LCMS detects(M+H)+=209.

Part B. Preparation of 6-tert-Butyl-4-chloro-thieno[3,2-d]pyrimidine

6-tert-Butyl-thieno[3,2-d]pyrimidin-4-ol (500 mg, 2.40 mmol, 1 eq.) andphosphorous oxychloride (4.48 mL, 48.0 mmol, 20 eq.) were refluxed undernitrogen for 1.5 hours. Stripped 3× from methylene chloride thendissolved in methylene chloride and rinsed 3× with saturated NaHCO3, 1×with brine. Dried and stripped in vacuo to give 250 mg of amber solidsas product. LCMS detects (M+H)+=227.

Example 112 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 6-tert-butyl-4-chloro-thieno[3,2-d]pyrimidine. Purified by HPLC togive 6.0 mg of white solids as title product. LCMS detects (M+H)+=598.

Example 113 Part A. Preparation of6-tert-Butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ol

3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (0.50 g,2.34 mmol, 1 eq.) and trifluoroacetamidine (263 mg, 2.34 mmol, 1 eq.)were heated neat at 150° C. until reaction was complete by TLC. Cooledto rt then dissolved resultant solids in chloroform. Dried and strippedin vacuo to give 540 mg of white solids as product. LCMS detects(M+H)+=277.

Part B. Preparation of6-tert-Butyl-4-chloro-2-trifluoromethyl-thieno[3,2-d]pyrimidine

Followed the procedure of Example 112 Part B starting from6-tert-Butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ol. LCMS detects(M+H)+=295.

Example 113 Part C Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from6-tert-butyl-4-chloro-2-trifluoromethyl-thieno[3,2-d]pyrimidine.Purified by HPLC. LCMS detects (M+H)+=666.

Example 114 Part A. Preparation of Ethyl3-(tert-Butyl)-pyrrole-5-carboxylate

The above compound was synthesized by the methods disclosed in Example129 employing tert-butylchloride in place of 1-chloroadamantane andforegoing the initial 30 minute heating period. MS found: (M+H)+=196.28.

Part B. Preparation of Ethyl 3-tert-Butyl-1-aminopyrrole-5-carboxylate

Preparation of monochloramine by the Method of John Hynes, Jr., et al.,J. Org. Chem., 2004, in press: NH₄Cl (3 g, 56 mmol, was mixed in ether(110 mL) and cooled to −5° C. Concentrated NH₄OH (4.7 mL) was then addedfollowed by dropwise addition of bleach (Chlorox, 72 mL) over 15minutes. The mixture was stirred for 15 minutes, the layers separatedand the organic layer washed with brine. The organic layer was driedover powdered CaCl₂ in the freezer for 1 h and used for the subsequentstep immediately.

Ethyl 3-(tert-butyl)pyrrole-5-carboxylate (obtained from Part A) (1.67g, 8.6 mmol, 1 eq) was dissolved in DMF. Sodium hydride (60% suspensionin oil) (0.41 g, 10 mmol, 1.2 eq) was then added thereto cautiously andstirred for 45 minutes at RT under nitrogen. Monochloramine was thenadded (0.15M in ether, 68.4 mL, 10 mmol, 1.2 eq). The next morning, thereaction is quenched with saturated aqueous Na₂S₂O₃, diluted with waterand extracted into ether. The ether layer is dried, filtered andstripped to yield 3.19 g of product as a yellow oil which eventuallycrystallized as long needles. MS found: (M+H)+=211.34.

Part C. Preparation of 6-tert-Butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol

Ethyl 3-tert-Butyl-1-aminopyrrole-5-carboxylate (1.00 g, 4.76 mmol, 1eq), formamidine acetate (1.46 g, 14.3 mmol, 3 eq.) and ethoxyethanol(10 mL) were mixed and refluxed for 3 hours. The solvent was strippedand then restripped from chloroform (3×) to yield a solid. This solidwas stirred in 5 mL MeOH, filtered, and the collected solids rinsed withEt₂O and dried to yield 233 mg of a white solid as product. LCMS found:(M+H)+⁺=191.

Part D. Preparation of6-tert-Butyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine

The compound from Part C immediately above (0.43 mg, 2.26 mmol, 1 eq.)and POCl3 (4.21 mL, 45.2 mmol, 20 eq.) were mixed and refluxed for 4hours. The mixture was stripped then restripped 3× from methylenechloride and then dissolved in methylene chloride and rinsed 3× withsat'd NaHCO₃, 1× with brine. Dried and stripped in vacuo to give 490 mgof an amber oil. LCMS detects (M+H)+=210.

Example 114 Part E. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-pyrrolidin-2-one

The above compound was synthesized using the procedure of Example 106Part C starting from of6-tert-Butyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine. LCMS detects(M+H)+581.

Example 115 Part A. Preparation of6-Adamant-1-yl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine

The above compound was prepared from ethyl3-(adamanty-1-yl)-pyrrole-5-carboxylate by the procedures in Example114, parts A, B, and C beginning with ethyl3-(Adamanty-1-yl)-pyrrole-5-carboxylate (Example 129). Mass found:(M+H)+⁺=288.22.

Example 115 Part B. Preparation of(3S)-3-(6-Adamantan-1-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one

3S-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(49 mg, 0.12 mmol, 1 eq),6-adamant-1-yl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.18 mmol,1.5 eq), triethylamine (0.066 mL, 0.48 mmol, 4 eq) and ethanol (1.7 mL)were microwaved at 100° C. for 1 hour. The contents were stripped andflash chromatographed in 100% EtOAc to 4:1 chloroform/methanol to yield49 mg of a white powder. This powder was taken up in methylene chlorideand washed with water (3×). The organic layer was dried and stripped toyield 30 mg of a white powder. Mass found: (M+H)+⁺=659.49.

Example 116 Part A. Preparation of 2-Phenyl-3H-imidazole-4-carboxylicacid methyl ester

Phenylamidoxime (5.00 g, 36.7 mmol, 1 eq.), methyl propriolate (3.27 mL,36.7 mmol, 1 eq.), and methanol (25 mL) were refluxed overnight undernitrogen. The reaction was stripped 2× from toluene. Added diphenylether (20 mL then heated at 200° C. overnight. Cooled to rt. Added ethylacetate (50 mL). Rinsed 2× with brine. The organic layer was dried andstripped in vacuo to give an amber oil. Triturated solids with diethylether. Obtained 2.84 g of tan solids as product. LCMS detects(M+H)+=203.

Part B. Preparation of 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acidmethyl ester and 1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid methylester

2-Phenyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.24 mmol,1 eq.) was dissolved in THF (10 mL) at rt under nitrogen then cooled to0° C. Potassium hexamethyldisilazane (0.5 M in toluene) (2.72 mL, 1.36mmol, 1.1 eq.) was added dropwise via an addition funnel. Stirred 10minutes. Added iodomethane (85 mL, 1.36 mmol, 1.1 eq.). Stirredovernight at rt. Added saturated NH₄Cl (20 mL), and extracted 2× withmethylene chloride. The organic layers were combined, dried and strippedin vacuo to give 225 mg of an amber oil as product. LCMS detects(M+H)+=217.

Part C. Preparation of 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acidand 1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid

3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester and itsisomer (225 mg, 1.04 mmol, 1 eq.), 4 N NaOH (1.30 mL, 5.20 mmol, 5 eq.)and THF (5 mL) were mixed at rt then refluxed for 2 hours then stirredovernight at rt. Stripped off the THF, added water then rinsed 1× withdiethyl ether. The basic aqueous pH was adjusted to 3 with conc. HCl.The aqueous was then extracted 3× with chloroform (10 mL). Thechloroform layers were combined, dried and stripped in vacuo to give 30mg of a film as product. LCMS detects (M+H)+=203.

Example 116 Part D. Preparation of3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt and 1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(and other isomer) (50 mg, 0.124 mmol, 1 eq.),3-methyl-2-phenyl-3H-imidazole-4-carboxylic acid (30 mg, 0.148 mmol, 1.2eq.), 1-hydroxybenzotriazole hydrate (HOBT) (20 mg, 0.148 mmol, 1.2eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (28 mg,0.148 mmol, 1.2 eq.), triethylamine (35 μL, 0.247 mmol, 2 eq.) and THF(5 mL were stirred at rt under nitrogen overnight. Purified by LCMS.Obtained 50 mg of white solids as product. LCMS detects (M+H)+=592.

Example 117 Part A. Preparation of3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester and1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid methyl ester

2-Phenyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.24 mmol,1 eq.) was dissolved in THF (10 mL) at rt under nitrogen then cooled to0° C. Potassium hexamethyldisilazane (0.5 M in toluene) (2.72 mL, 1.36mmol, 1.1 eq.) was added dropwise via an addition funnel. Stirred 10minutes. Added benzylbromide (0.16 mL, 1.36 mmol, 1.1 eq.). Stirredovernight at rt. Added saturated NH₄Cl (20 mL), and extracted 2× withmethylene chloride. The organic layers were combined, dried and strippedin vacuo to give 200 mg of an amber oil as product. LCMS detects(M+H)+=293.

Part B. Preparation of 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acidand 1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid

3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester (200 mg,0.684 mmol, 1 eq.) and other isomer, 4 N NaOH (0.86 mL, 3.42 mmol, 5eq.) and THF (5 mL) were mixed at rt then refluxed for 2 hours thenstirred overnight at rt. Stripped off the THF, added water then rinsed1× with diethyl ether. The basic aqueous pH was adjusted to 3 with conc.HCl. The aqueous was then extracted 3× with chloroform (10 mL). Thechloroform layers were combined, dried and stripped in vacuo to give 390mg of an amorphous solid as product. LCMS detects (M+H)+=279.

Example 117 Part C. Preparation of3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt and 1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt

Followed the procedure of Example 116, Part D starting from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 3-benzyl-2-phenyl-3H-imidazole-4-carboxylic acid and its otherisomer. Obtained 21 mg of off-white solids as product. LCMS detects(M+H)+=668.

Example 118 Preparation of 2-Phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt

3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid{(3S*)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amideand its other isomer (15 mg) 5 mL methanol, and 20% Pd(OH)₂ (10 mg) werehydrogenated until completion by TLC on a Parr shaker at 50 psi.Filtration through fiberglass filter paper under nitrogen and removal ofsolvent in vacuo yielded 6 mg of product. LCMS detects (M+H)+=578.

Example 119 Part A. Preparation of 6,7-Dimethoxy-quinazolin-4-ol

Followed the procedure of Example 107 Part A starting from2-amino-4,5-dimethoxy-benzoic acid. LCMS detects (M+H)+=207.

Part B. Preparation of 4-Chloro-6,7-dimethoxy-quinazoline

6,7-Dimethoxy-quinazolin-4-ol (1.00 g, 4.85 mmol, 1 eq.), phosphorousoxychloride (4.07 mL, 43.6 mmol, 9.00 eq.) and triethylamine (6.08 mL,43.6 mmol, 9 eq.) were refluxed for 2 hours. Stripped then restripped 3×from methylene chloride then dissolved in methylene chloride and rinsed3× with saturated sodium bicarbonate, 1× with brine. Dried and strippedin vacuo to give an amber oil. Purified over silica gel in 9:1 to 3:1Hexanes/EtOAc. Obtained 0.84 g of off-white solids as product. LCMSdetects (M+H)+=225.

Example 119 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6,7-dimethoxy-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4-chloro-6,7-dimethoxy-quinazoline. LCMS detects (M+H)+=596.

Example 120 Part A. Preparation of 6-Fluoro-quinazolin-4-ol

Followed the procedure of Example 107 Part A starting with2-amino-5-fluorobenzoic acid. ¹H NMR (400 MHz) (CD₃OD) ? 8.06 (s, 1H),7.87 (m, 1H), 7.75 (m, 1H), 7.62 (m, 1H).

Part B. Preparation of 4-Chloro-6-fluoro-quinazoline

Followed the procedure of Example 112 Part B starting with6-fluoroquinazolin-4-ol. LCMS detects (M+H)+=183.

Example 120 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-fluoro-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4-chloro-6-fluoro-quinazoline. Purified by HPLC. LCMS detects(M+H)+=554.

Example 121 Part A. Preparation of 6-Methyl-quinazolin-4-ol

Followed the procedure of Example 107 Part A starting from2-Amino-5-methyl-benzoic acid. ¹H NMR (400 MHz) (CD₃OD) δ 8.00 (m, 2H),7.68 (d, 1H, J=7 Hz), 7.59 (d, 1H, J=7 Hz), 2.47 (s, 3H).

Part B. Preparation of 4-Chloro-6-methyl-quinazoline

Followed the procedure of Example 111 Part B starting with6-methylquinazolin-4-ol. LCMS detects (M+H)+=179.

Example 121 Part B. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4-chloro-6-methyl-quinazoline. Purified by HPLC. LCMS detects(M+H)+=550.

Example 122 Part A. Preparation of 6-Phenyl-thieno[2,3-d]pyrimidin-4-ol

Followed the procedure of Example 112 Part A starting from2-Amino-5-phenyl-thiophene-3-carboxylic acid methyl ester. LCMS detects(M+H)+=229.

Part B. Preparation of 4-Chloro-6-phenyl-thieno[2,3-d]pyrimidine

Followed the procedure of Example 112 Part B starting with6-Phenyl-thieno[2,3-d]pyrimidin-4-ol. LCMS detects (M+H)+=247.

Example 122 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand of 4-chloro-6-phenyl-thieno[2,3-d]pyrimidine. Purified by HPLC. LCMSdetects (M+H)+=618.

Example 123 Part A. Preparation of 2-Butyrylamino-5-chloro-benzamide

2-Amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq.), 1.000 N NaOH (6.50mL, 6.5 mmol, 1 eq.) and THF (20 mL) were mixed and stirred at 0° C. Tothis mixture was added butyryl chloride dropwise (0.68 mL, 6.50 mmol, 1eq.). More acid chloride and base were added to drive reaction tocompletion. The reaction was allowed to warm to rt. After 4 days thereaction was worked up by adding ethyl acetate, washing with 1 N HCl(3×), saturated sodium bicarbonate (1×), and brine (1×). The organiclayer was dried and stripped to yield 1.44 g of a white powder asproduct. LCMS detects (M+H)+=241.0.

Part B. Preparation of 6-Chloro-2-propyl-quinazolin-4-ol

2-Butyrylamino-5-chloro-benzamide (1.08 g, 4.49 mmol, 1 eq.), 1.000 NNaOH (13.46 mL, 13.5 mmol, 3 eq.) and ethanol (10 mL) were mixed andstirred at rt for 15 minutes. The mixture was acidified to pH=2 with1.000 N HCl. The mixture was extracted with ethyl acetate. Solids thatdid not dissolve were filtered and rinsed with diethyl ether to dry.Obtained 810 mg of a white solid product. LCMS detects (M+H)+=223.

Part C Preparation of 4,6-Dichloro-2-propyl-quinazoline

6-Chloro-2-propyl-quinazolin-4-ol (810 mg, 3.64 mmol, 1 eq.),phosphorous oxychloride (3.30 mL, 35.1 mmol, 9.64 eq.) and triethylamine(1.63 mL, 11.7 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3×from methylene chloride then dissolved in methylene chloride and rinsed3× with saturated sodium bicarbonate, 1× with brine. Dried and strippedin vacuo to give an amber oil. Purified over silica gel in 9:1Hexanes/EtOAc. Obtained 510 mg of off-white solids as product. Theproduct was used immediately in Example 121 Part D.

Example 123 Part D. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4,6-dichloro-2-propyl-quinazoline using the conditions described inExample 106 Part C. MS (ES+)=613 (M+H)⁺.

Example 124 Part A. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-isopropyl-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

The above compound was synthesized from isobutyryl chloride using theprocedures found in Example 123, Parts A-D. MS (ES+)=612 (M+H)⁺.

Example 125 Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2-tert-butyl-6-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

The above compound was synthesized from 2,2-Dimethyl-propionyl chlorideusing the procedures found in Example 123, Parts A-D. LCMS detects(M+H)+=626.

Example 126 Part A. Preparation of 6-Chloro-2-methyl-quinazolin-4-ol

2-Amino-5-chlorobenzoic acid (3.58 g, 20.9 mmol, 1 eq.), acetamidinehydrochloride (2.36 g, 25.1 mmol, 1.2 eq.) and 2-ethoxyethanol (70 mL)were mixed and refluxed for 48 h. The resultant solids were filtered anddried to yield 1.57 g of yellow solid product. MS (ES+)=195/197 (M+H)+⁺.

Part B. Preparation of 4,6-Dichloro-2-methyl-quinazoline

6-Chloro-2-methyl-quinazolin-4-ol (0.75 g, 3.90 mmol, 1 eq.),phosphorous oxychloride (3.47 mL, 37.4 mmol, 9.64 eq.) and triethylamine(1.62 mL, 12.5 mmol, 3.21 eq.) were refluxed for 4 hours. The mixturewas stripped twice from toluene and the residue dissolved in ethylacetate. The organic layer was washed with saturated NH₄Cl (2×), driedand stripped. The residue was flash chromatographed in 3:2 ethylacetate/hexanes to yield 400 mg of a light yellow solid product. MS(ES+)=213/215/217 (M+H)+⁺.

Example 126 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one

The above compound was synthesized following the procedure of Example106 Part C using the product from Part B immediately above. MS (ES+)=585(M+H)+⁺.

Example 127 Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-ethyl-quinazolin-4-ylamino)-pyrrolidin-2-one

The above compound was synthesized by the procedures in Example 126beginning with propionamidine hydrochloride. MS (ES+)=599 (M+H)+⁺.

Example 128 Part A. Preparation of{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester

(1S,2R,4R)-2-Benzenesulfonylmethyl-N4-isopropyl-N4-methyl-cyclohexane-1,4-diamine(300 mg, 0.93 mmol, 1 eq.), L-N—BOC-Aspartic acid (216 mg, 0.93 mmol,1.0 eq.), 1-hydroxybenzotriazole hydrate (HOBT) (275 mg, 2.03 mmol, 2.2eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (390mg, 2.03 mmol, 2.2 eq.), triethylamine (0.39 mL, 2.77 mmol, 3 eq.) andmethylene chloride (15 mL) were stirred at 0° C. and allowed to warm tort under nitrogen overnight. The mixture was washed with 2 N sodiumcarbonate, water (1×) and the organic layer dried and stripped. Theresidue was purified over silica gel in 100% ethyl acetate to 4:1methylene chloride/methanol to 4:1 methylene chloride/2N NH3 inmethanol. Obtained 60 mg of product. LCMS detects (M+H)+=522.

Part B. Preparation of(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidine-2,5-dione

{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (60 mg), TFA (1 mL), and methylene chloride (3 mL)were mixed and stirred overnight at rt. The mixture was stripped andrestripped from methylene chloride (3×) to yield 60 mg of an oil. LCMSdetects (M+H)+=374.

Example 128 Part C. Preparation ofN-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide,TFA salt

(3S)-3-Amino-1-[((1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidine-2,5-dione(60 mg, 0.092 mmol, 1 eq), 3-trifluoromethylbenzoyl chloride (0.014 mL,0.092 mmol, 1 eq.), triethylamine (0.039 mL, 0.28 mmol, 3 eq.) and THF(3 mL) were mixed and stirred at rt with the acid chloride being addedlast. The reaction mixture was stripped and purified by LCMS to yield5.5 mg of product. LCMS detects (M+H)+=594.

Example 129 Part A. Preparation of Ethyl3-(Adamanty-1-yl)-pyrrole-5-carboxylate

Ethyl pyrrole-2-carboxylate (2.09 g, 15 mmol, 1 eq), was added to amixture of gallium(III) chloride (2.90 g, 16.5 mmol, 1.1 eq) in carbondisulfide (40 mL) and the contents heated at 40° C. for 30 min.Afterwards, 1-chloroadamantane (2.82 g, 16.5 mmol, 1.1 eq), was addedthereto and the contents heated for another 40 minutes. The reaction waspoured onto a mixture of ice and 1N HCl, and extracted with chloroform.The extracts were washed with saturated sodium bicarbonate, dried(MgSO4) and the solvent stripped to yield a crude solid.

Recrystallization from EtOAc yielded 2 crops. 1^(st) crop wt.=0.67grams. 2^(nd) crop wt.=1.10 grams. MS found: (M+H)+=274.44 and 274.45,respectively.

Part B. Preparation of 3-(Adamanty-1-yl)-pyrrole-5-carboxylic Acid

The compound obtained from Part A immediately above (0.29 g, 1.1 mmol, 1eq), 1.000 N NaOH (2.20 mL, 2.2 mmol, 2 eq) and MeOH (15 mL) were mixedand stirred overnight. After only partial reaction, more 1.000 N NaOH(21 mL) together with more MeOH to dissolve were added and the contentsrefluxed for 4 hours. The contents were acidified to pH=1 with 1H HCl.The MeOH was stripped off to yield solids and aqueous. The mixture wasextracted with EtOAc, the EtOAc layers were combined, washed with brine,dried (MgSO₄) and stripped to yield 250 mg of a white powder. MS found:(M+H)+=246.44.

Example 129 Part C. Preparation ofN-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1H-pyrrole-2-carboxamide,TFA salt

(3S)-1-[1S,2R,4R-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(45 mg, 0.11 mmol, 1 eq), 3-(adamanty-1-yl)-pyrrole-5-carboxylic acid(27 mg, 0.11 mmol, 1 eq), HOBT (15 mg, 0.11 mmol, 1 eq),1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCI) (21mg, 0.11 mmol, 1 eq), and methylene chloride (5 mL) were mixed andstirred overnight. The contents were stripped and purified by LCMS.Lyophillization yielded 45 mg of a white solid. MS found:(M+H)+=635.58.s

Example 130 Part A. Preparation of Ethyl3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate

Ethyl 3-(adamanty-1-yl)-pyrrole-5-carboxylate (obtained from Example129) (0.20 g, 0.7 mmol, 1 eq) was dissolved in THF (20 mL). Potassiumbis(trimethylsilyl)amide (0.5 M in Tol, 1.62 mL, 0.81 mmol, 1.1 eq) wasadded thereto followed by iodomethane (0.102 mL, 1.6 mmol, 2.2 eq). Thenext day, the same amounts of potassium bis(trimethylsilyl)amide andiodomethane were again added to drive the reaction to completion. In 4h, the reaction was finished. Ethyl acetate was added (100 mL) and theorganic layer was washed with water (2×), brine, dried (MgSO4) andstripped to yield 600 mg of product which was used as is in the nextstep. MS found: (M+H)⁺=288.16.

Part B. Preparation of 3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate

Saponification of ethyl 3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate(entire contents from Part A) by the procedure in Example 129 Part Byielded 160 mg of product. MS found: (M−H)+=258.10.

Example 130 Part C. Preparation ofN-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1-methyl-1H-pyrrole-2-carboxamide,TFA salt

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(49 mg, 0.12 mmol, 1 eq), 3-(adamanty-1-yl)-pyrrole-5-carboxylic acid(31 mg, 0.12 mmol, 1 eq), HOBT (16 mg, 0.12 mmol, 1 eq),1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCI) (23mg, 0.11 mmol, 1 eq), and methylene chloride (5 mL) were mixed andstirred overnight. The contents were stripped and dissolved in EtOAc,washed with 1N HCl (1×), 1N NaOH (2×), brine (1×), dried and stripped.The residue was flash chromatographed in 1:1 hexane/EtOAc to 100% EtOActo 4:1 chloroform/methanol to yield 31 mg of a yellow glass. MS found:(M+H)+=649.32.

Example 131 Part A. Preparation of5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid

A 22% solution of sodium ethoxide in ethanol (53 mL, 165 mmol) was addeddropwise to a magnetically stirred suspension of tert-butylcarbamadinehydrochloride (20.0 g, 146 mMol) in ethanol (100 mL). When the additionwas complete, the yellow suspension was warmed to 50° C., the heatingmantle was removed, and a solution of mucobromic acid (15.7 g, 61 mMol)in ethanol (50 mL) was added dropwise at a rate which did not allow thetemperature to exceed 55° C. When this addition was complete, a 22%solution of sodium ethoxide in ethanol (32 mL, 98 mMol) was addeddropwise, then the mixture was allowed to cool to room temperature. Thesuspension was filtered, the solids were rinsed with ethanol (2×20 mL),and the combined filtrates were concentrated in-vacuo. The residue thusobtained was stirred in 2 N aqueous HCl (30 mL). The resulting solidswere collected by filtration, rinsed with ice-cold water (2×20 mL), andair dried to yield 12.1 g of a beige powder as product. MS (ES+)=259,261 (M+H)⁺. Yield=76%.

Part B. Preparation of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acidmethyl ester

A 2.0 M hexanes solution of trimethylsilyldiazomethane (11.8 mL, 23.62mMol) was added dropwise to a stirring solution of5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (6.12 g, 23.62 mmol)in 9:1 benzene/methanol (100 mL), and the reaction was stirred for 2days. TLC analysis showed that the reaction was complete, so the mixturewas concentrated in-vacuo. The residue was dissolved in ethyl acetate(100 mL), washed with water (3×20 mL), dried over sodium sulfate, thenconcentrated in-vacuo. Purified over silica gel, eluting with 10% ethylacetate/hexanes, to yield 5.2 g of a colorless oil as product. MS(ES+)=273, 275 (M+H)⁺. Yield=81%.

Part C. Preparation of5-tert-Butoxycarbonylamino-2-tert-butyl-pyrimidine-4-carboxylic acidmethyl ester

A flame dried reaction tube charged with tert-butylcarbamate (140 mg,1.2 mmol), cesium carbonate (456 mg, 1.4 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthane (18 mg, 0.03 mMol), andtris(dibenzylidineacetone)dipalladium(0) (19 mg, 0.02 mMol) wasevacuated under vacuum, then backfilled with argon. Dioxane (2 mL) and5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid methyl ester (273 mg,1.0 mMol) were added, and the mixture was degassed under vacuum. Thetube was then backfilled with argon, sealed, and heated at 100° C. for 2hours. Analysis by LC/MS showed complete consumption of startingbromide. The mixture was diluted with methylene chloride (20 mL),filtered to remove solids, and concentrated in-vacuo. The residue waspurified over silica gel, eluting with 10% ethyl acetate/heptane, toyield 152 mg of white solids as product. MS (ES+)=310 (M+H)⁺. Yield 50%.

Part D. Preparation of 5-Amino-2-tert-butyl-pyrimidine-4-carboxylic acidmethyl ester, HCl salt

5-tert-Butoxycarbonylamino-2-tert-butyl-pyrimidine-4-carboxylic acidmethyl ester (2.4 g, 7.75 mMol) was dissolved in a 4 M solution of HClin dioxane (30 mL). After 10 minutes of stirring, a thick white solidprecipitated. The reaction was allowed to stir overnight, during whichtime the mixture became a homogenous, amber solution. Concentratedin-vacuo, and the residue was stripped from toluene (2×50 mL) followedby methylene chloride (3×50 mL) to remove excess HCl. The resulting 1.85g of yellow solids was used without further purification in the nextstep. MS (ES+)=210 (M+H)⁺.

Part E. Preparation of 6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol

A mixture of 5-amino-2-tert-butyl-pyrimidine-4-carboxylic acid methylester, HCl salt (1.1 g, 4.48 mMol) and formamidine acetate (1.86 g,17.90 mMol) in 2-ethoxyethanol (20 mL) was heated at reflux for 5 hours.LC/MS analysis showed the reaction to be essentially complete, so themixture was cooled to room temperature, then concentrated in-vacuo. Theresidue was purified over silica gel, eluting with ethyl acetate, 1%methanol/ethyl acetate, then 2% methanol/ethyl acetate to yield 1.06 gof a beige solid as product. MS (ES+)=205 (M+H)⁺. Yield=94%.

Part F. Preparation of 2-tert-Butyl-8-chloro-pyrimido[5,4-d]pyrimidine

6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol (210 mg, 1.03 mMol) wasdissolved in phosphorous oxychloride (10 mL), and the mixture was heatedat reflux for 4 hours. The solution was concentrated in-vacuo, thenstripped from methylene chloride (3×50 mL) to remove excess phosphorousoxychloride. The residue was stirred for 10 minutes in saturated sodiumbicarbonate (50 mL), then extracted with ethyl acetate (3×30 mm). Thecombined organic phases were washed with water (30 mL), followed bybrine (30 mL), dried over sodium sulfate, then concentrated in-vacuo.The residue was purified over silica gel, eluting with 50% ethylacetate/heptane, to yield 150 mg of a white solid as product. NMR (500MHz, CDCl3) δ 9.61 (s, 1H), 9.15 (s, 1H), 1.52 (s, 9H).

Example 131 Part G. Preparation of1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-pyrimido[5,4-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 2-tert-butyl-8-chloro-pyrimido[5,4-d]pyrimidine using the conditionsdescribed in JBS Example 106, Part C. MS (ES+)=594 (M+H)⁺.

Example 132 Example 132 Preparation of5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(93 mg, 0.23 mmol), 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid,(60 mg, 0.23 mMol), HOBT (68 mg, 0.50 mmol), triethylamine (96 μL, 0.69mMol), and EDCI (96 mg, 0.50 mMol) were combined in CH₂Cl₂ (2 mL), andthe mixture was stirred overnight at room temperature. The mixture wasdiluted with ethyl acetate (15 mL), and washed with saturated NaHCO₃(3×5 mL), water (5 mL), and brine (5 mL). The organic phase was driedover sodium sulfate, and concentrated in-vacuo. The residue was purifiedby reverse phase HPLC, using a Phenomenex Luna 10μ, C18 (2), 250×50 mmcolumn, under the following conditions: 10% to 70% acetonitrile in water(0.05% TFA in each solvent) over 30 minutes. The reaction yielded 13 mgof white powder as product. MS (ES+)=570 (M+H).

Example 133 Preparation of 2-tert-Butyl-pyrimidine-4-carboxylic acid{(3S*)-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt

A solution of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt (30 mg, 0.04 mMol) in methanol (10 mL) was hydrogenated at 50psi in the presence of 1 N aqueous sodium hydroxide (80 μL, 0.08 mMol)and 10% palladium on activated carbon (20 mg) for 2 hours. The catalystwas removed by filtration, and the filtrate was concentrated in-vacuo.The residue was purified by reverse phase HPLC, using a Phenomenex Luna10μ, C18 (2), 250×50 mm column, under the following conditions: 10% to70% acetonitrile in water (0.05% TFA in each solvent) over 30 minutes.The reaction yielded 25 mg of white powder as product. MS (ES+)=648(M+H).

Example 134 Preparation of 2-tert-Butyl-5-phenyl-pyrimidine-4-carboxylicacid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt

5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide,TFA salt (80 mg, 0.10 mMol), phenyl boronic acid (26 mg, 0.21 in mMol),and 2.0 M aqueous K₃PO₄ solution (210 μL, 0.42 mMol) were combined in 2mL of DMF in a microwave reaction tube, and the solution was degassedunder vacuum, then backfilled with argon.

Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.01 mMol) was added,and the mixture was again degassed as described above. The tube wassealed, and the reaction mixture was heated via microwave at 150° C. for30 minutes. The reaction was cooled, some solids were removed byfiltration and rinsed with ethyl acetate, and the combined filtrateswere concentrated in-vacuo. The residue was purified by reverse phaseHPLC, using a Phenomenex Luna 10μ, C18 (2), 250×50 mm column, under thefollowing conditions: 10% to 70% acetonitrile in water (0.05% TFA ineach solvent) over 30 minutes. The reaction yielded 27 mg of whitepowder as product. MS (ES+)=646 (M+H).

Example 135 Part A. Preparation of 3-tert-Butyl-benzoic acid

A mixture of the commercially available methyl3-bromo-5-tert-butylbenzoate (700 mg, 2.58 mMol), aqueous NaOH (1 N,7.75 mL, 7.75 mMol), and Pearlman's catalyst (100 mg) in methanol (20mL) was hydrogenated at 50 psi for 22 hours. The catalyst was removed byfiltration and rinsed with a small amount of methanol. The filtrate wasconcentrated in-vacuo to remove methanol, and the aqueous mixture wasacidified with 1 N HCl (10 mL), then extracted with ethyl acetate (3×20mL). The combined organic phases were dried over sodium sulfate, thenconcentrated in-vacuo. Analysis of the resulting material by LC/MSshowed that the ester had hydrolyzed to the carboxylic acid, but thatthe bromide was still present. The material was dissolved in methanol(20 mL), and hydrogenated overnight at 50 psi in the presence of 1 Naqueous NaOH (5.2 mL, 5.2 mMol) and 10% palladium on activated carbon(50 mg). Analysis of the crude reaction mixture by LC/MS showed that thebromine was still present, so Pearlman's catalyst (200 mg) was added,and hydrogenation at 50 psi was continued for 23 hours. MS showed thatthe reaction was now complete, so the reaction was worked up asdescribed previously in this example to yield 376 mg of white powder asproduct. MS (AP−)=177 (M−H)+⁺. Yield=81%.

Example 135 Part B. Preparation of N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-tert-butyl-benzamide,TFA salt

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 3-tert-Butyl-benzoic acid using the conditions described in Example132. MS (ES+)=568 (M+H).

Example 136 Part A. Preparation of Lithium 3-bromo-5-tert-butylbenzoate

A solution of the commercially availablemethyl-3-bromo-5-tert-butylbenzoate (87 mg, 0.32 mMol) in THF (2 mL) wastreated with 0.5 N aqueous lithium hydroxide (0.71 mL, 0.35 mMol), andthe mixture was stirred at room temperature for six hours. The THF wasstripped in-vacuo, and the aqueous solution was freeze dried to yield112 mg of light brown solids. This material was used as-is in the nextstep.

Example 136 Part B. Preparation of N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-bromo-5-tert-butyl-benzamide,TFA salt

(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one(39 mg, 0.10 mmol), lithium-3-bromo-5-tert-butylbenzoate (25 mg, 0.10mMol), diisoproplyethylamine (84 μL, 0.48 mMol), and HATU (37 mg, 0.10mMol) were combined in CH₂Cl₂ (2 mL), and the mixture was stirredovernight at room temperature. The mixture was diluted with ethylacetate (15 mL) and washed with saturated NaHCO₃ (3×5 mL), water (5 mL),and brine (5 mm). The organic phase was dried over sodium sulfate, andconcentrated in-vacuo. The residue was purified by reverse phase HPLC,using a Phenomenex Luna 10μ, C18 (2), 250×50 mm column, under thefollowing conditions: 10% to 70% acetonitrile in water (0.05% TFA ineach solvent) over 30 minutes. The reaction yielded 17 mg of whitepowder as product. MS (ES+)=647 (M+H)⁺.

Example 137 Part A. Preparation of Pyrido[2,3-d]pyrimidin-4-ol

A mixture of 2-aminonicotinic acid (880 mg, 6.4 mMol) and formamidineacetate (2.0 g, 19.1 mMol) in 2-ethoxyethanol (25 mm) was heated atreflux overnight. The solution was allowed to come to room temperatureand stand for 2 hours, then the resulting precipitate was collected byfiltration, rinsed with 2-ethoxy ethanol (2×5 mL), diethyl ether (20mL), and air dried to yield 525 mg of a gray powder as product. MS(ES+)=148 (M+H)⁺. Yield=56%.

Part B. Preparation of 4-Chloro-pyrido[2,3-d]pyrimidine

A solution of pyrido[2,3-d]pyrimidin-4-ol (490 mg, 3.33 mmol),triethylamine (4.4 mL, 31.6 mMol), and phosphorous oxychloride (2.8 mL,30 mMol) was heated at reflux for 2 hours. The mixture was concentratedin-vacuo, and the residue was stripped from methylene chloride (3×50 mL)to remove excess phosphorous oxychloride. The residue was dissolved inethyl acetate (100 mm), saturated sodium bicarbonate (100 mL) was addedcarefully, causing vigorous gas evolution, and the mixture was stirredfor ten minutes. The layers were separated, the organic phase was washedwith saturated sodium bicarbonate (30 mL), water (30 mL), brine (30 mL),dried over sodium sulfate, then concentrated in-vacuo. The residue waspurified over silica gel, eluting with 40% ethyl acetate/heptane, toyield 92 mg of a tan solid as product. MS (ES+)=166 (M+H)⁺. Yield=17%.

Example 137 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4-Chloro-pyrido[2,3-d]pyrimidine using the conditions described inExample 106, Part C. MS (ES+)=537 (M+H)⁺.

Example 138 Part A. Preparation of 2-Amino-nicotinic acid ethyl ester

A 60% sodium hydride suspension in mineral oil (1.28 g, 32 mMol) wasadded to a stirring suspension of 2-aminonicotinic acid (4.21 g, 30mMol) in DMF (50 mL), and the mixture was gently heated until gasevolution was observed. The suspension was stirred at room temperaturefor 4 hours, after which a homogeneous amber solution was observed.Iodoethane (4.75 g, 30 mmol) was added, and the mixture was allowed tostir overnight at room temperature. The solution was concentratedin-vacuo, the residue was taken up in 9:1 ethyl acetate/hexane (200 mL),washed with water (5×50 mL), and brine (50 mL), dried over sodiumsulfate, then concentrated in-vacuo. The residue was purified oversilica gel, eluting with 25%-50% ethyl acetate/hexane, to yield 3.6 g ofcolorless solids as product. NMR (500 MHz, DMSO) δ 8.20 (dd, 1H, J=5 Hz,2 Hz), 8.06 (dd, 1H, J=8 Hz, 2 Hz), 7.16 (s, 2H), 6.63 (dd, 1H, J=8 Hz,5 Hz), 4.28 (q, 2H, J=7 Hz), 1.30 (t, 3H, J=7 Hz). Yield=72%.

Part B. Preparation of 2-Amino-5-chloro-nicotinic acid ethyl ester

A solution of 2-amino-nicotinic acid ethyl ester (3.60 g, 21.7 mMol) inmethanol (100 mL) was treated with HCl gas via sparge tube for 5minutes, causing the colorless solution to turn yellow. The solution wasconcentrated in-vacuo, then stripped from methanol (2×50 mL) to removeexcess HCl. The residue was dissolved in methanol (100 mL), treated withtert-butyl hypochlorite (2.6 g, 23.8 mMol), and the mixture was allowedto stir overnight at room temperature. Analysis by TLC showed that somestarting material remained, so additional tert-butyl hypochlorite (0.47g, 4.3 mMol) was added, and stirring was continued overnight. Analysisby TLC showed that all starting material had been consumed. The solutionwas concentrated in-vacuo, the residue was taken up in methylenechloride (150 mL), washed with saturated sodium bicarbonate (3×50 mL),5% aqueous sodium thiosulfate (3×50 mL), water (50 mL), brine (50 mL),dried over sodium sulfate, and concentrated in-vacuo. The residue waspurified over silica gel, eluting with 20%-30% ethyl acetate/heptane, toyield 1.50 g of colorless solids as product. MS (AP+)=201 (M+H)⁺.Yield=35%.

Part C. Preparation of 6-Chloro-pyrido[2,3-d]pyrimidin-4-ol

A mixture of 2-amino-5-chloro-nicotinic acid ethyl ester (1.5 g, 7.38mMol) and formamidine acetate (3.1 g, 29.51 mMol) in 2-ethoxyethanol (50mL) was heated at reflux overnight. The solution was cooled to roomtemperature, and allowed to stand for 2 hours. The resulting precipitatewas collected by filtration, rinsed with a small amount of2-ethoxyethanol followed by diethyl ether (10 mL), and allowed to airdry. The filtrate was concentrated in-vacuo, and the residue wastriturated with methylene chloride. The resulting solids were combinedwith the solids from the earlier filtration, and this material wascrystallized from methanol to yield 475 mg of tan needles as product, inthree crops. MS (ES+)=182 (M+H)⁺. Yield=37%.

Part D. Preparation of 4,6-Dichloro-pyrido[2,3-d]pyrimidine

The titled compound was prepared from6-Chloro-pyrido[2,3-d]pyrimidin-4-ol using the conditions described inExample 131, Part F. MS (ES+)=201 (M+H)⁺. Yield=85%.

Example 138 Part E. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4,6-Dichloro-pyrido[2,3-d]pyrimidine using the conditions describedin Example 106, part C. MS (ES+)=572 (M+H)⁺.

Example 139 Part A. Preparation of6-Chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ol

The titled compound was prepared from 2-Amino-5-chloro-nicotinic acidethyl ester and trifluoromethylacetamidine using the conditionsdescribed in Example 113, part A. MS (ES+)=250 (M+H)⁺.

Part B. Preparation of4,6-Dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine

The titled compound was prepared from6-Chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ol using theconditions described in Example 131, part F. MS (ES+)=268 (M+H)⁺.

Example 139 Part C. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one.

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand 4,6-dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine using theconditions described in Example 106, part C. MS (ES+)=639 (M+H)⁺.

Example 140 Part A. Preparation of (4-Trifluoromethoxy-phenyl)-carbamicacid tert-butyl ester

A solution of 4-(trifluoromethyl)phenyl isocyanate (9.75 g, 48.0 mMol)in THF (100 mL) was cooled to 0° C., and a 1.0 M THF solution ofpotassium tert-butoxide (53 mL, 53 mMol) was added dropwise. The mixturewas allowed to warm to room temperature, and stirred for 7 hours. Thesolution was poured into a mixture of saturated ammonium chloridesolution (200 mL), and diethyl ether (200 mL). Enough water was added toredissolve the ammonium chloride that had crashed out, the mixture wasshaken in a separatory funnel, and the layers were separated. Theorganic phase was washed with saturated ammonium chloride (100 mL),water (100 mL), brine (100 mL), dried over sodium sulfate, andconcentrated in-vacuo. The residue was purified over silica gel, elutingwith 10%-20% ethyl acetate/heptane to yield 11.7 g of white solids asproduct. NMR (500 MHz, DMSO) δ 9.54 (s, 1H), 7.54 (d, 2H, J=7 Hz), 7.23(d, 21, J=8 Hz), 1.45 (s, 9H). Yield=88%.

Part B. Preparation of2-tert-Butoxycarbonylamino-5-trifluoromethoxy-benzoic acid

A solution of (4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester(2.31 g, 8.33 mMol) in anhydrous THF (50 mL) at −78° C. was treated witha 1.4 M solution of sec-butyllithium in cyclohexane (13 mL, 18.33 mMol),at a rate which did not allow the internal temperature to exceed −60° C.The solution was stirred at −78° C. for 15 minutes, then allowed to warmto −40° C. and stirred for 2.5 hours. The reaction was treated withgaseous CO₂, stirred 30 minutes while warming to −20° C., then quenchedwith saturated ammonium chloride. The mixture was warmed to roomtemperature, and extracted with ethyl acetate (3×50 mL). The combinedorganic phases were washed with water (50 mL), brine (50 ml), dried oversodium sulfate, and concentrated in-vacuo. The residue was trituratedwith hot heptane to yield 1.9 g of white powder as product. NMR (500MHz, DMSO) δ 12.89 (s, 1H), 8.24 (d, 1H, J=9 Hz), 7.84 (s, 1H), 7.21 (d,1H, J=7 Hz), 1.51 (s, 9 Hz). Yield=72%.

Part C. Preparation of 2-Amino-5-trifluoromethoxy-benzoic acid, HCl salt

2-tert-Butoxycarbonylamino-5-trifluoromethoxy-benzoic acid (1.9 g, 5.91mMol) was dissolved in a 4 N HCl solution in dioxane (15 mL), and theresulting suspension was stirred at room temperature for 6 hours.Analysis by LC/MS showed that the reaction was incomplete, soconcentrated HCl (1 ml) was added, followed by methylene chloride (20mL) to dissolve the solids, and the reaction was stirred overnight atroom temperature. The mixture was concentrated in-vacuo, then strippedfrom methanol (3×50 mL) to remove any excess HCl. The resulting solidswere used as-is in the next step. MS (ES+)=222 (M+H)⁺.

Part D. Preparation of 6-Trifluoromethoxy-quinazolin-4-ol

A mixture of 2-amino-5-trifluoromethoxy-benzoic acid, HCl salt (1.52 g,5.91 mmol), and formamidine acetate (1.84 g, 17.73 mMol) in2-ethoxyethanol (20 mL) was heated at reflux for 2 hours. Analysis byLC/MS showed that the reaction was complete, so the mixture wasconcentrated in-vacuo, and the residue was purified over silica gel,eluting with 50% ethyl acetate/heptane-100% ethyl acetate, to yield 1.1g of white solids as product. MS (ES+)=231 (M+H)⁺. Yield=82%.

Part E. Preparation of 4-Chloro-6-trifluoromethoxy-quinazoline

The titled compound was prepared from 6-trifluoromethoxy-quinazolin-4-olusing the conditions described in example 137, part B. MS (ES+)=249(M+H)⁺.

Example 140 Part F. Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-trifluoromethoxy-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,TFA salt

The titled compound was prepared from(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-oneand of 4-chloro-6-trifluoromethoxy-quinazoline using the conditionsdescribed in example 106, part C. MS (ES+)=620 (M+H)⁺.

Example 141 Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-methylamino-quinazolin-4-ylamino)-pyrrolidin-2-one,TFA salt

1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one(35 mg, 0.0487 mmol, 1 eq.), 2.0 M mono-methylamine in THF (1.22 mL,2.44 mmol, 50 eq.), and THF (1 mL) were microwaved at 100° C. untilreaction was complete by LCMS. Purified by HPLC. Obtained 60 mg of whitesolids as product. LCMS detects (M+H)+=599.

Example 142 Preparation of(3S)-3-(6-Fluoro-quinazolin-4-ylamino)-1-[(1S,2R,4R)-4-(isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-2-one,TFA salt

Followed the procedure of Example 106 Part C starting from(3S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-2-one(10c) and 4-chloro-6-fluoro-quinazoline. Purified by HPLC. LCMS detects(M+H)+=568.

Example 143 Preparation ofN-{1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-(3S)-3-yl}-2-chloro-5-trifluoromethyl-benzamide,TFA salt

Followed the procedure of Example 116 Part D starting from2-chloro-5-trifluoromethyl-benzoic acid. Purified by HPLC. LCMS detects(M+H)+=614.

The next step: ESI MS m/z 507 [C₂₆H₂₉F₃N₂O₃S+H]⁺.

Example 144(S)-3-(6-Bromoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one,TFA salt

(144a) 6-Bromo-4-chloroquinazoline was incorporated into Example 106,Part C give the title compound. MS found (M+H)⁺=615.

Example 145(S)-3-(6,7-Difluoroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one,TFA salt

(145a) 4-Chloro-6,7-difluoroquinazoline was incorporated into Example106, Part C give the title compound. MS found: (M+H)⁺=572.

Example 146(S)-3-(6-Methoxyquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one,TFA salt

(146a) 4-Chloro-6-methoxyquinazoline was incorporated into Example 106,Part C give the title compound. MS found: (M+H)⁺=566.

Example 147((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(quinazolin-4-ylamino)pyrrolidin-2-one,TFA salt

(147a) 4-Chloroquinazoline was incorporated into Example 106, Part Cgive the title compound. MS found: (M+H)⁺=536.

Example 1483-Phenyl-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide,TFA salt

(148a) 3-Phenyl-benzoic acid was incorporated into Example 132 give thetitle compound. MS found: (M+H)⁺=588.

Example 149(S)-3-(6-Iodoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one,TEA salt

(149a) 4-Chloro-6-iodoquinazoline was incorporated into Example 106,Part C give the title compound. MS found (M+H)⁺=662.

Example 1503-Tert-butyl-4-hydroxy-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide,TFA salt

(150a) 3-Tert-butyl-4-hydroxybenzoic acid was incorporated into Example132 give the title compound. MS found: (M+H)⁺=584.

Example 1513-Amino-5-tert-butyl-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)thiophene-2-carboxamide,TFA salt

(151a) 3-Amino-5-tert-butylthiophene-2-carboxylic acid was incorporatedinto Example 132 give the title compound. MS found: (M+H)⁺=589.

Example 152N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-2-methyl-5-phenylfuran-3-carboxamide,TFA salt

(152a) 2-Methyl-5-phenylfuran-3-carboxylic acid was incorporated intoExample 132 give the title compound. MS found: (M+H)⁺=592.

Example 153N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-nitrofuran-2-carboxamide,TFA salt

(153a) 5-Nitrofuran-2-carboxylic acid was incorporated into Example 132give the title compound. MS found: (M+H)⁺=547.

Example 154N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-4-phenylthiophene-2-carboxamide,TFA salt

(154a) 4-Phenylthiophene-2-carboxylic acid was incorporated into Example132 give the title compound. MS found: (M+H)⁺=594.

Example 155N—((S)-2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyrrolidin-1-yl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide,TFA salt

(155a) Tert-butyl(S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate(52c) (80 mg) was dissolved in DMF prior to the addition1,4-dibromobutane and K₂CO₃ (75 mg). After 16 h, water and EtOAc wereadded. The organic layer was dried, filtered, and concentrated. Theresulting residue was dissolved in CH₂Cl₂ (2 mL) and cooled to 0° C.prior to the addition of TEA (2 mL). After the reaction was warmed to rtover 1 h, it was concentrated and dried. This material was dissolved inDMF prior to the addition of (iPr)₂NEt (0.03 mL) and3-trifluoromethylbenzoic acid (33 mg). After cooling to 0° C., HATU (78mg) was added. The resulting mixture was warmed to rt and was stirredovernight. The solution was diluted with EtOAc and was washed with sat.NaHCO₃. The organic phase was dried (MgSO₄), filtered, and concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (5 mg). MS found: (M+H)⁺=578.3.

Table 1 contains representative examples of the present invention. Eachof the following structural formulas are to be used in the indicatedexample (Ex) range paired with the given R¹ and R² substituent. The R¹and R² described in the tables may be the same or different than thosedescribed in the claims TABLE 1

EX. 1-2

EX. 3,17,18,20,21

EX. 4,6

EX. 5,7,9,22,23,27,56,57,60

EX. 8

EX. 10-15

EX. 16

EX. 19,34

EX. 24,25

EX. 26

EX. 28,29,32

EX. 30,31

EX. 33

EX. 35,36

EX. 37

Ex. 38

Ex. 39,40

Ex. 41,42,45,46

Ex. 47-51

Ex. 52,53,63-72

Ex. 58,59

Ex. 61,62,73-84,155

Ex. 85-92,97-101

Ex. 93-96

Ex. 102-105 MS Ex R¹ R² [M + H]  1 4-(methylthio)phenyl2-(t-butoxycarbonyl)amino- 635.4 5-trifluoromethylphenyl M + H  24-(methylthio)phenyl 2-amino-5- 535.4 trifluoromethylphenyl M + H  34-methylphenyl 3-trifluoromethylphenyl 594.3  4 4-methylphenyl3-trifluoromethylphenyl 594.3  5 methyl 3-trifluoromethylphenyl 580.3  6phenyl 3-trifluoromethylphenyl 580.3  7 ethyl 3-trifluoromethylphenyl594.3  8 phenyl 3-trifluoromethylphenyl 594.3  9 cyclopropylmethyl3-trifluoromethylphenyl 620.3 10 azido 3-trifluoromethylphenyl 610.5 11amino 3-trifluoromethylphenyl 584.5 12 isopropylamino3-trifluoromethylphenyl 626.6 13 isopropyl(methyl)amino3-trifluoromethylphenyl 640.6 14 isopropyl(propargyl)3-trifluoromethylphenyl 664.6 amino 15 isopropyl(cyclopropyl3-trifluoromethylphenyl 680.6 methyl)amino 16 4-(methylthio)phenyl3-trifluoromethylphenyl 640.3 17 4-(methylthio)phenyl3-trifluoromethylphenyl 626.3 18 4-(methylthio)phenyl3-(trifluoromethyl)phenyl 641.3 amino 19 4-(methylthio)phenyl3-(trifluoromethyl)phenyl 662.3 sulfonyl 20 4-(methylthio)phenyl phenyl558.3 21 phenyl 3-(trifluoromethyl)phenyl 595.3 amino 22 H3-trifluoromethylphenyl 566.4 23 allyl 3-trifluoromethylphenyl 606.3 24H 3-trifluoromethylphenyl 566.3 25 H 3-trifluoromethylphenyl 566.5 264-(methylthio)phenyl 2-(t-butoxycarbonyl)amino- 621.45-trifluoromethylphenyl 27 propyl 3-trifluoromethylphenyl 608.3 284-(methylthio)phenyl 3-trifluoromethylphenyl 581   29 phenyl3-trifluoromethylphenyl 535   30 isopropyl(methyl)amino3-trifluoromethylphenyl 595.4 31 amino 3-trifluoromethoxyphenyl 555.2 324-(methylthio)phenyl 3-trifluoromethoxyphenyl 597.2 334-(methylthio)phenyl 3-trifluoromethylphenyl 537   344-(methylthio)phenyl 3-(trifluoromethyl)phenyl 612.3 methylene 35 H3-(trifluoromethyl)phenyl NMR ethylene 36 H 3-(trifluoromethyl)phenyl551.4 ethylene 37 methyl 3-trifluoromethylphenyl 608   38 methyl3-trifluoromethylphenyl 566   39 methyl 3-trifluoromethylphenyl 623   40methyl 3-trifluoromethylphenyl 623   41 methyl O 579   42 methyl O 579  43 methyl OH 581   44 methyl OH 581   45 methyl methoxyamino 608   46methyl methoxyamino 608   47 amino trifluoromethyl 521   48isopropylamino trifluoromethyl 563   49 isopropyl(methyl)aminotrifluoromethyl 577   50 isopropyl(ethyl)amino trifluoromethyl 591   51diethylamino trifluoromethyl 577   52 isopropyl(methyl)amino1-naphthalenyl 534   53 isopropyl(methyl)amino 3-benzo[b]thiophenyl540   54 isopropyl(methyl)amino 6-chloroquinazolin-4-yl 570.2 55isopropyl(methyl)amino 6,8-dichloroquinazolin-4-yl 604.2 56 methyl3,5-dichlorophenyl 580   57 methyl 3-trifluoromethoxylphenyl 596.2 58methyl H 563   59 methyl methyl 577   60 methyl phenyl 512   61isopropyl(methyl)amino 3,5-bis-trifluoromethyl- 648   phenyl 62isopropyl(methyl)amino 2-amino-5-trifluoro- 611   methoxyphenyl 63isopropyl(methyl)amino 6-trifluoromethylquinolin- 603.2 4-yl 64isopropyl(methyl)amino 6-trifluoromethylquinolin- 603.2 4-yl 65isopropyl(methyl)amino 7-trifluoromethylquinolin- 603.2 4-yl 66isopropyl(methyl)amino 7-trifluoromethylquinolin- 603.2 4-yl 67isopropyl(methyl)amino 2-phenyl-phenyl 560.3 68 isopropyl(methyl)amino3,5-bis-trifluoromethyl- 620.2 phenyl 69 isopropyl(methyl)amino2-trifluoromethylphenyl 552.3 70 isopropyl(methyl)amino2-trifluoromethoxyphenyl 568.3 71 isopropyl(methyl)amino3-trifluoromethylphenyl 552.3 72 isopropyl(methyl)amino4-trifluoromethylphenyl 552.3 73 isopropyl(methyl)amino 3-chlorophenyl546   74 isopropyl(methyl)amino 3-fluoro-5- 648   trifluoromethylphenyl75 t-butoxycarbonylamino 3-trifluoromethylphenyl 624.7 76 phenyl3-trifluoromethylphenyl 600.1 77 pyridin-3-yl 3-trifluoromethylphenyl601   78 thiazolin-2-yl 3-trifluoromethylphenyl 607   79methoxycarbonylamino 3-trifluoromethylphenyl 582.2 80 formamidyl3-trifluoromethylphenyl 552.3 81 aminocarbonylamino3-trifluoromethylphenyl 567.3 82 (methylamino)carbonyl3-trifluoromethylphenyl 581.3 amino 83 2-oxo-pyrrolidin-1-yl3-trifluoromethylphenyl 592   84 1,1-dioxido- 3-trifluoromethylphenyl628   isothiazolidin-2-yl 85 4-chlorophenyl 3-fluoro-5- 632  trifluoromethylphenyl 86 4-chlorophenyl 3-chlorophenyl 580   874-chlorophenyl 3,5-bis- 683   trifluoromethylphenyl 88 4-chlorophenyl2-tert- 746   butoxycarbonylamino-5- trifluoromethoxyphenyl 894-chlorophenyl 2-amino-5- 645   trifluoromethoxyphenyl 90 4-chlorophenyl3-trifluoromethoxyphenyl 630.2 91 4-chlorophenyl 3-trifluoromethylphenyl614.0 92 4-chlorophenyl 3,5-bis-chloro-phenyl 614.2 93 4-chlorophenyl3-chlorophenyl 596   94 4-chlorophenyl 3-trifluoromethylphenyl 630.3 954-chlorophenyl 3-fluoro-5- 649.1 trifluoromethylphenyl 96 phenyl3-trifluoromethylphenyl 596.3 97 4-isopropyl-phenyl3-trifluoromethylphenyl 622.3 98 2-methyl-phenyl 3-trifluoromethylphenyl594.6 99 4-fluoro-phenyl 3-trifluoromethylphenyl 598.5 100 4-methyl-phenyl 3-chloro-phenyl 560.2 101  4-methyl-phenyl 2-amino-5-625.2 trifluoromethoxyphenyl 102  amino 3-trifluoromethylphenyl 493.4103  isopropylamino 3-trifluoromethylphenyl 535.2 104 isopropyl(methyl)amino 3-trifluoromethylphenyl 548.7 105 isopropyl(ethyl)amino 3-trifluoromethylphenyl 563.3 155  pyrrolidin-1-yl3-trifluoromethylphenyl 578.3

TABLE A

No. R MS 144

615 145

572 146

566 137

537 147

536 140

620 120

554 138

572 139

639 131

594 135

568 132

648 136

647 150

584 133

570 148

588 134

646 121

550 109

613 110

586 111

604 112

598 113

666 122

618 124

612 115

659 151

539 152

592 153

547 154

594 116

592 117

668 118

577 143

614 129

636 130

649 119

596 125

626 126

585 127

599 106

638 123

613 141

599 107

570 108

604 114

581 149

662

TABLE B

142

568

TABLE C

128

594

UTILITY

Compounds of formula I are shown to be modulators of chemokine receptoractivity using assays know by those skilled in the art. In this section,we describe these assays and give their literature reference. Bydisplaying activity in these assays of MCP-1 antagonism, compounds offormula I are expected to be useful in the treatment of human diseasesassociated with chemokines and their cognate receptors. The definitionof activity in these assays is a compound demonstrating an IC₅₀ of 20 μMor lower in concentration when measured in a particular assay.

Antagonism of MCP-1 Binding to Human PBMC

(Yoshimura et al., J. Immunol. 1990, 145, 292)

Compounds of the present invention have activity in the antagonism ofMCP-1 binding to human PBMC (human peripheral blood mononuclear cells)described here.

Millipore filter plates (#MABVN1250) are treated with 100 μl of bindingbuffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mM magnesiumchloride in RPMI 1640 media) for thirty minutes at room temperature. Tomeasure binding, 50 μl of binding buffer, with or without a knownconcentration compound, is combined with 50 μl of ¹²⁵-I labeled humanMCP-1 (to give a final concentration of 150 pM radioligand) and 50 μl ofbinding buffer containing 5×10⁵ cells. Cells used for such bindingassays can include human peripheral blood mononuclear cells isolated byFicoll-Hypague gradient centrifugation, human monocytes (Weiner et al.,J. Immunol. Methods. 1980, 36, 89), or the THP-1 cell line whichexpresses the endogenous receptor. The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and the plates washedthree times with binding buffer containing 0.5M NaCl. The plastic skirtis removed from the plate, the plate allowed to air dry, the wellspunched out and counted. The percent inhibition of binding is calculatedusing the total counts obtained in the absence of any competing compoundand the background binding determined by addition of 100 nM MCP-1 inplace of the test compound.

Antagonism of MCP-1-Induced Calcium Influx

(Sullivan, et al. Methods Mol. Biol., 114, 125-133 (1999)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced calcium influx assay described here.

Calcium mobilization is measured using the fluorescent Ca²⁺ indicatordye, Fluo-3. Cells are incubated at 8×10⁵ cells/ml in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mMglucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and 2.5 mM probenecid for60 minutes at 37° C. Cells used for such calcium assays can includehuman monocytes isolated as described by Weiner et al., J. Immunol.Methods, 36, 89-97 (1980) or cell lines which expresses the endogenousCCR2 receptor such as THP-1 and MonoMac-6. The cells are then washedthree times in phosphate-buffered saline containing 0.1% bovine serumalbumin, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid. The cells areresuspended in phosphate-buffered saline containing 0.5% bovine serumalbumin, 20 mM HEPES and 2.5 mM probenecid at a final concentration of2-4×10⁶ cells/ml. Cells are plated into 96-well, black-wall microplates(100 μl/well) and the plates centrifuged at 200×g for 5 minutes. Variousconcentrations of compound are added to the wells (50 μl/well) and after5 minutes, 50 μl/well of MCP-1 is added to give a final concentration of10 nM. Calcium mobilization is detected by using a fluorescent-imagingplate reader. The cell monolayer is excited with an argon laser (488 nM)and cell-associated fluorescence measured for 3 minutes, (every secondfor the first 90 seconds and every 10 seconds for the next 90 seconds).Data are generated as arbitrary fluorescence units and the change influorescence for each well determined as the maximum minimumdifferential. Compound-dependent inhibition is calculated relative tothe response of MCP-1 alone.

Antagonism of MCP-1-Induced Human PBMC Chemotaxis

(Bacon et al., Brit. J. Pharmacol. 1988, 95, 966)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced human PBMC chemotaxis assay described here.

Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC 96 wellplate, and Neuroprobe polyvinylpyrrolidone-free polycarbonate PFDS8-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl. 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. To start the assay, add the MCP-1/compound mixture into thewells of the Polyfiltronics MPC 96 well plate that has been placed intothe bottom part of the Neuroprobe chemotaxis chamber. The approximatevolume is 400 μl to each well and there should be a positive meniscusafter dispensing. The 8 micron filter is placed gently on top of the 96well plate, a rubber gasket is attached to the bottom of the upperchamber, and the chamber is assembled, A 200 μl volume of the cellsuspension/compound mixture is added to the appropriate wells of theupper chamber. The upper chamber is covered with a plate sealer, and theassembled unit is placed in a 37° C. incubator for 45 minutes. Afterincubation, the plate sealer is removed and all the remaining cellsuspension is aspirated off. The chamber is disassembled and the filtergently removed. While holding the filter at a 90 degree angle,unmigrated cells are washed away using a gentle stream of phosphatebuffered saline and the top of the filter wiped with the tip of a rubbersqueegee. Repeat this wash twice more. The filter is air dried and thenimmersed completely in Wright Geimsa stain for 45 seconds. The filter isthen washed by soaking in distilled water for 7 minutes, and then a 15second additional wash in fresh distilled water. The filter is again airdried. Migrated cells on the filter are quantified by visual microscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostoma braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases.

In addition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for promoters of chemokinereceptor function if one contemplates the delivery of sufficientcompound to cause the loss of receptor expression on cells through theinduction of chemokine receptor internalization or delivery of compoundin a manner that results in the misdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The compounds of the present invention are used to treat or preventdisorders selected from rheumatoid arthritis, osteoarthritis, septicshock, atherosclerosis, aneurism, fever, cardiovascular effects,haemodynamic shock, sepsis syndrome post ischemic reperfusion injury,malaria, Crohn's disease, inflammatory bowel diseases, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, autoimmune diseases, skininflammatory diseases, multiple sclerosis, radiation damage, hyperoxicalveolar injury, HIV, HIV dementia, non-insulin dependent diabetesmellitus, asthma, allergic rhinitis, atopic dermatitis, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,Hodgkin's disease, colonic carcinoma, Felty's syndrome, sarcoidosis,uveitis, Alzheimer, Glomerulonephritis, and systemic lupuserythematosus.

In another aspect, the compounds are used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, aneurism, fever, cardiovasculareffects, Crohn's disease, inflammatory bowel diseases, psoriasis,congestive heart failure, multiple sclerosis, autoimmune diseases, skininflammatory diseases.

In another aspect, the compounds are used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, Crohn's disease, inflammatory boweldiseases, and multiple sclerosis.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention may be used. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient.

Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, or alternatively fromabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, or between about 0.01 to 100mg/kg of body weight per day, or alternatively, between about 1.0 to 20mg/kg/day. Intravenously, the doses will range from about 1 to about 10mg/kg/minute during a constant rate infusion. Compounds of thisinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three, or four timesdaily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Dosage forms(pharmaceutical compositions) suitable for administration may containfrom about 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration maycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compoundsof this invention are combined with other anticoagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula I and about 1 to 7.5 milligrams of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 milligrams per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination. Particularly when provided as asingle dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵; X is selectedfrom O or S; Z is selected from a bond, —NR⁸C(O)—, —NR⁸C(S)—,—NR⁸C(O)NH—, —NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —C(O)NR⁸—, —OC(O)NR⁸—,—NR⁸C(O)O—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—, —C(O)CR¹⁵R¹⁵—,CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—,—CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—S(O)_(p)—, and—S(O)_(p)—NR⁹—; wherein neither Z nor R¹³ are connected to a carbon atomlabeled (b); bond (a) is a single or double bond; alternatively, when nis equal to 2, two atoms labeled (b) may join through a double bond; Eis selected from —S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—, —C(O)—NR^(e)—,—NR^(e)C(O)NR^(e), SO₂—NR^(e)—, and —NR^(e)SO₂NR^(e)—; R^(e) isindependently selected from H and C₁₋₃ alkyl; R¹ is selected from aC₆₋₁₀ aryl group substituted with 0-5 R⁶ and a 5-10 membered heteroarylsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5R⁷ and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁷; R⁴ is selected fromH, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CRR)_(t)OH, (CRR)_(t)SH,(CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),(CR′R′)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4d), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(t)NR^(4a)S(O)₂R^(4b), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4e), and a (CHR)_(r)-4-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(4e); R^(4a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-4 R^(4e), and a (CHR)_(r)-4-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(4e); R^(4b), at each occurrence, isselected from H, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenylsubstituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(4e), and a(CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(4e); R^(4c) isindependently selected from —C(O)R^(4b), —C(O)OR^(4d),—C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4d), at each occurrence, isselected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3R^(4e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e);R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j), —C(O)NR^(4h)R^(4h),—OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and(CH₂)_(r)phenyl; R^(4f), at each occurrence, is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,and a (CH₂)_(r)—C₃₋₁₀ carbocyclic; R^(4i), at each occurrence, isselected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a(CH₂)_(r)OC₃₋₆ carbocyclic residue; R^(4j), at each occurrence, isselected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀carbocyclic residue; R⁵, at each occurrence, is independently selectedfrom H, ═O, CO_(—)6 alkyl, C₂₋₈ alkenyl, C₂₋₃ alkynyl, (CRR)_(r)OH,(CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)N(→O)R^(5a)R^(5a), N₃, (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b),(CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),(CRR)_(r)OC(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)OR^(5d),(CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)H,(CRR)_(r)C(O)OR^(5d), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),(CRR)_(r)S(O)₂N^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b),(CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5c), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(5c); R^(5a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(5g), C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(e); R^(5b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-3 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(5e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),(CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)OC(O)NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b),(CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b),(CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from—C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), —CN, and (CH₂)_(r)phenyl;R, at each occurrence, is selected from H, C₁₋₅ alkyl substituted withR^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN; (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)N^(6a)R^(6a),(CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); alternatively, two R⁶ on adjacentatoms on R¹ may join to form a cyclic acetal; R^(6a), at eachoccurrence, is selected from H, methyl substituted with 0-1 R^(6g), C₂₋₆alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6b), at each occurrence, isselected from H, C₁₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(6e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(6e); R^(6d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(6e),C₃₋₈ alkynyl substituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(6e), C₂₋₄ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e); R^(6e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and(CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g) is independently selectedfrom —C(O)R^(6b), —C(O)OR^(6d), —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)C₃₋₁₀ carbocyclic residue and (CR′R′)_(r)phenyl substitutedwith 0-3 R^(7e); alternatively, two R⁷ on adjacent atoms on R² may jointo form a cyclic acetal; R^(7a), at each occurrence, is independentlyselected from H, methyl substituted with 0-1 R^(7g), C₂₋₆ alkylsubstituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e); R^(7b), at each occurrence, is selectedfrom C₁₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a(CH₂)_(r)-5-5 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃, C₂₋₄ haloalkyl,C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,C(O)OC₁₋₅ alkyl, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(7g) is independently selectedfrom —C(O)R^(7b), —C(O)OR^(7d), —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(6e); R⁸ is selected from H, C₁₋₄alkyl, and C₃₋₄ cycloalkyl; R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄cycloalkyl, —C(O)H, and —C(O)—C₁₋₄alkyl; R¹⁰ is independently selectedfrom H, and C₁₋₄alkyl substituted with 0-1 R^(10b), alternatively, twoR¹⁰ form ═O; R^(10b), at each occurrence, is independently selected from—OH, —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ isselected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R¹¹d, (CHR)_(r)C(O)R^(11b),(CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),(CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),(CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),(CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(11e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11a), at each occurrence, is independently selected fromH, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); R^(11b), ateach occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11d), at each occurrence, is independently selected fromH, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆carbocyclic residue substituted with 0-3 R^(11e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and(CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹² is selected from H, C₁₋₄ alkyl,(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d),(CHR)_(r)C(O)R^(12b), (CHR)_(r)NR^(12a)R^(12a),(CHR)_(r)C(O)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)OR^(12d),(CHR)_(q)R^(12a)C(O)R^(12b), (CHR)_(q)NR^(12a)C(O)OR^(12d),(CHR)_(q)CC(O)NR^(12a)R^(12a), (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-5 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); R^(12b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl,C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(12e),and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl; R^(12f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹³, ateach occurrence, is independently selected from H, and C₁₋₄alkylsubstituted with 0-1 R^(13b), —OH, —NH₂, F, Cl, Br, I, —OR^(13a),—N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3 R^(13b); R^(13a) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R^(13b), at eachoccurrence, is independently selected from —OH, —SH, —N^(13c)R^(13c),—C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at each occurrence, isindependently selected from H and C₁₋₄alkyl; alternatively, two R¹⁴s,along with the carbon atom to which they are attached, join to form aC₃₋₆ carbocyclic ring; R¹⁵, at each occurrence, is independentlyselected from H, C₁₋₄alkyl, OH, NH₂, O—C₁₋₄ alkyl, NR^(15a)R^(15a),C(O)NR^(15a)R^(15a), NR^(15a)C(O)R¹Sb, NR^(15a)C(O)OR^(15d),OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d); alternatively, twoR¹⁵s, along with the carbon atom or atoms to which they are attached,join to form a C₃₋₆ carbocyclic ring; R^(15a), at each occurrence, isindependently selected from H, and C₁₋₄ alkyl; R^(15b), at eachoccurrence, is independently selected from C₁₋₄ alkyl, C₃₋₆ alkenyl, andC₃₋₆ alkynyl; R^(15d), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl; R¹⁶ is selected fromC₁₋₄ alkyl; l is selected from 1, 2 and 3; n is selected from 0, 1, 2,and 3; m is selected from 0 and 1; p, at each occurrence, isindependently selected from 0, 1, and 2; q, at each occurrence, isindependently selected from 1, 2, 3, and 4; r, at each occurrence, isindependently selected from 0, 1, 2, 3, and 4; t, at each occurrence, isindependently selected from 2, 3, and 4; s is selected from 0 and
 1. 2.A compound of claim 1, wherein the compound is of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein thecycloalkyl group is saturated or partially unsaturated; or a heterocycleof 3 to 7 atoms wherein the heterocycle is saturated or partiallyunsaturated, the heterocycle containing a heteroatom selected from —O—,—S—, —S(═O)—, S(═O)₂—, and —N(R⁴)—, the heterocycle optionallycontaining a —C(O)—; ring B being substituted with 0-2 R⁵; X is selectedfrom O or S; Z is selected from a bond, —NR⁸C(O)—, —NR⁸C(S)—,—NR⁸C(O)NH—, —NR⁸C(S)NH—, —NR⁸SO₂, —N⁸SO₂NH—, —C(O)NR⁸—, —OC(O)NR⁸—,—NR⁸C(O)O, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═CR¹⁴—, —CR¹⁵R¹⁵C(O)—, —C(O)CR¹⁵R¹⁵—,CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —O—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—,—CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—S(O)_(p)—, and—S(O)_(p)—NR⁹—; wherein neither Z nor R¹³ are connected to a carbon atomlabeled (b); bond (a) is a single or double bond; alternatively, when nis equal to 2, two atoms labeled (b) may join through a double bond; Eis selected from —S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—, —C(O)—NR^(e)—,NR^(e)C(O)NR^(e)—, SO₂—NR^(e)—, and —NR^(e)SO₂NR^(e)—; R^(e) isindependently selected from H and C₁₋₃ alkyl; R¹ is selected from aC₆₋₁₀ aryl group substituted with 0-5 R⁶ and a 5-10 membered heteroarylsystem containing 14 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5R⁷ and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁷; R⁴ is selected fromH, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CRR)_(t)OH, (CRR)_(t)SH,(CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),(CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4d), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(t)NR^(4a)S(O)₂R^(4b), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4e), and a (CHR)_(r)-4-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(4e); R^(4a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-4 R^(4e), and a (CHR)_(r)-4-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(4e); R^(4b), at each occurrence, isselected from H, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenylsubstituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(4e), and a(CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(4e); R^(4c) isindependently selected from —C(O)R^(4b), —C(O)OR^(4d),—C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4d), at each occurrence, isselected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3R^(4e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e);R^(4e), at each occurrence, is selected from C₁₋₅ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j), —C(O)NR^(4h)R^(4h),—OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and(CH₂)_(r)phenyl; R^(4f), at each occurrence, is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,and a (CH₂)_(r)—C₃₋₁₀ carbocyclic; R^(4i), at each occurrence, isselected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue; R^(4j), at each occurrence, isselected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀carbocyclic residue; R⁵, at each occurrence, is independently selectedfrom H, ═O, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH,(CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5d),(CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5d), (CRR)_(r)OC(O)R^(5b),(CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),(CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), C₁₋₆haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c);R^(5a), at each occurrence, is independently selected from H, methylsubstituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),C₃₋₈ alkenyl substituted with 0-2 R^(5a), C₃₋₈ alkynyl substituted with0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(5e); R^(5c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),(CH₂)rOC(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄alkyl, (CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b),(CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b),(CH₂)_(r)NHC(NR⁵)NR⁵ f R⁵ f (CH₂)_(r)S(O)₂NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)S(O)₂—R^(5b), and (CH₂)_(r)phenyl substituted with 0-3R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected fromC(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R, ateach occurrence, is selected from H, C₁₋₆ alkyl substituted with R^(5e),C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(s)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(5e); alternatively, two R⁶ on adjacentatoms on R¹ may join to form a cyclic acetal; R^(6a), at eachoccurrence, is selected from H, methyl substituted with 0-1 R^(6g), C₂₋₆alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6b), at each occurrence, isselected from H, C₁₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(6e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(6e); R^(6d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(6e),C₃₋₈ alkynyl substituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(6e), C₂₋₄ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e); R^(6e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and(CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g) is independently selectedfrom —C(O)R^(6b), —C(O)OR^(6d), —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(7e); alternatively, two R⁷ onadjacent atoms on R² may join to form a cyclic acetal; R^(7a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenylsubstituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃,C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3 R^(7e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SN, C(O)OC₁₋₅ alkyl, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(7g)is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′, at each occurrence, isselected from H, C₁₋₆ alkyl substituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted withR^(6e); R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R⁹ isselected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H, and—C(O)—C₁₋₄alkyl; R¹⁰ is independently selected from H, and C₁₋₄alkylsubstituted with 0-1 R^(10b); R^(10b), at each occurrence, isindependently selected from —OH, —SH, —NR^(10c)R^(10c),—C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ is selected from H, C₁₋₄ alkyl,(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d),(CHR)_(r)C(O)R^(11b), (CHR)_(r)NR^(11a)R^(11a),(CHR)_(r)C(O)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)OR^(11d),(CHR)_(q)NR^(11a)C(O)R^(11b), (CHR)_(q)NR^(11a)C(O)OR^(11d),(CHR)_(r)OC(O)NR^(11a)R^(11a), (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl,C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(11e),and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² isselected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,(CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),(CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),(CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),(CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),(CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12a), at each occurrence, is independently selected fromH, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e); R^(12b), ateach occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substitutedwith 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12d), at each occurrence, is independently selected fromH, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and(CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹³, at each occurrence, is independentlyselected from H, and C₁₋₄alkyl substituted with 0-1 R^(13b), —OH, —NH₂,F, Cl, Br, I, —OR^(13a), —N(R^(13a))₂, and C₁₋₄ alkyl substituted with0-3 R^(13b); R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;R^(13b), at each occurrence, is independently selected from —OH, —SH,—NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄alkyl;alternatively, two R¹⁴s, along with the carbon atom to which they areattached, join to form a C₃₋₆ carbocyclic ring; R¹⁵, at each occurrence,is independently selected from H, C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl,NR^(15a)R^(15a), C(O)NR^(15a)R^(15a), NR^(15a)C(O)R^(15b),NR^(15a)C(O)OR^(15d), OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d);alternatively, two R¹⁵s, along with the carbon atom or atoms to whichthey are attached, join to form a C₃₋₆ carbocyclic ring; R^(15a), ateach occurrence, is independently selected from H, and C₁₋₄ alkyl;R^(15b), at each occurrence, is independently selected from C₁₋₄ alkyl,C₃₋₆ alkenyl, and C₃₋₆ alkynyl; R^(15d), at each occurrence, isindependently selected from C₁₋₄ alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;R¹⁶ is selected from C₁₋₄ alkyl; l is selected from 1, 2 and 3; n isselected from 0, 1, 2, and 3; m is selected from 0 and 1; p, at eachoccurrence, is independently selected from 0, 1, and 2; q, at eachoccurrence, is independently selected from 1, 2, 3, and 4; r, at eachoccurrence, is independently selected from 0, 1, 2, 3, and 4; t, at eachoccurrence, is independently selected from 2, 3, and 4; s is selectedfrom 0 and
 1. 3. The compound of claim 2, wherein m is
 0. 4. Thecompound of claim 3, wherein: ring B is selected from

 ring B being optionally substituted with 0-1 R⁵; and R¹¹ and R¹² are H.5. The compounds of claim 4, wherein: R⁵, at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d),(CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b),(CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),(CRR)_(r)N^(5a)C(O)OR^(5d), (CRR)_(r)OC(O)NR^(5a)R^(5a),(CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), CRR(CRR)_(r)NR^(5a)C(O)H,(CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),(CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆haloalkyl; R^(5a), at each occurrence, is independently selected from H,methyl, C₁₋₆ alkyl substituted with 0-2 R⁵⁶ wherein the alkyl isselected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, C₃alkenyl substituted with 0-1 R^(5e), wherein the alkenyl is selectedfrom allyl, C₃ alkynyl substituted with 0-1 R^(5e) wherein the alkynylis selected from propynyl, and a (CH₂)_(r)—C₃₋₄ carbocyclic residuesubstituted with 0-5 R^(5e), wherein the carbocyclic residue is selectedfrom cyclopropyl, and cyclobutyl; R^(5b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-2 R^(5e), wherein the alkylis selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, and hexyl, a (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with0-2 R^(5e), wherein the carbocyclic residue is selected fromcyclopropyl, and cyclobutyl; and R^(5d), at each occurrence, is selectedfrom methyl, CF₃, C₂₋₆ alkyl substituted with 0-2 R^(5e), wherein thealkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, and hexyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(5e).
 6. The compound of claim 5,wherein: R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CRR)_(t)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(r)NR^(4a)S(O)₂R^(4b); R, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e), R⁵, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a),(CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C(O)R^(5b),(CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b),and C₁₋₆ haloalkyl; R^(5a), at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,pentyl, hexyl, cyclopropyl, and cyclobutyl; and r, at each occurrence,is selected from 0, 1, and
 2. 7. The compound of claim 6, wherein: R¹ isselected from phenyl substituted with 0-2 R⁶, naphthyl substituted with0-2 R⁶, and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁶ wherein theheteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benzo[b]thiophene,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,pyrimido[5,4-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl; R² is selected fromphenyl substituted with 0-2 R⁷, and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁷ wherein the heteroaryl is selected from indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benzo[b]thiophene, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyridinyl,pyrimidinyl, pyrrolyl, pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl; R⁴ is selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,(CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),(CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),(CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),(CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),(CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b),(CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a),(CRR)_(r)NR^(4a)S(O)₂R^(4b); R^(4a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆alkyl substituted with 0-3 R^(4e) wherein C₂₋₆ is selected from ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl and hexyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-4 R^(4e) whereinthe carbocyclic residue is selected from cyclopropyl, cyclohexyl, andphenyl; R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; R^(4d) is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and cyclopropyl; and R⁸ is selected from H, methyl, ethyl, propyl,i-propyl, and cyclopropyl.
 8. The compound of claim 7, wherein: R⁶, ateach occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)N^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6a)C(O)NR^(6a)R^(6a),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)R^(6a), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted with0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);R^(6a), at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl and phenyl; R^(6b), at each occurrence, is selected frommethyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl, and phenyl; R^(5d), at each occurrence, is selected frommethyl, CF₃, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,hexyl, cyclopropyl, and phenyl; R^(6e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R^(6f), at each occurrence, is selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, andphenyl; R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,(CR′R′)_(r)O(CH)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,(CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, and(CR′R′)_(r)phenyl substituted with 0-3 R^(7e); R^(7a), at eachoccurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, hexyl, prop-2-enyl, 2-methyl-2-propenyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH₂cyclopropyl, andbenzyl; R^(7b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,pyrrolidinyl, morpholinyl, piperizinyl substituted with 0-1 R^(7e), andazetidinyl; R^(7d), at each occurrence, is selected from methyl, CF₃,CF₂CF₃, CHF₂, CH₂F, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, hexyl, and cyclopropyl; R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,C(O)OC₁₋₅ alkyl, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,cyclopropyl, and phenyl; and r is 0 or
 1. 9. The compound of claim 8,wherein: R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a),NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃,CHF₂, CH₂F, OCF₃, C(O)R^(7b), C(O)OR^(7d), NR^(7f)C(O)NR^(7a)R^(7a),NHS(O)₂R^(7b),


10. The compound of claim 9, wherein: ring B is selected from

 ring B being optionally substituted with 0-1 R⁵; Z is selected from abond, —NR⁸C(O)—, —C(O)NH—, and —NC(O)NH—; R¹ is selected from a C₆₋₁₀aryl group substituted with 0-3 R⁶ wherein the aryl group is selectedfrom phenyl and naphthyl, and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N and O, substituted with 0-3R⁶ wherein the heteroaryl system is selected from indolyl, pyridinyl,pyrimidinyl, pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,imidazyolyl, and pyrrolyl R² is phenyl substituted with 0-2 R⁷; R⁴ isselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, hexyl, and (CH₂)_(r)C(O)R^(4b); R⁶ is selected frommethyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO₂, CN,O(CH₂)_(r)R^(6d), C(O)H, C(O)R^(6d), C(O)OH, SR^(6d), NR^(6a)R^(6a),NC(O)R^(6b), OC(O)R^(6b), S(O)_(p)R^(6b), (CHR′)_(r)S(O)₂NR^(6a)R^(6a),and CF₃; R^(6a) is H, methyl, or ethyl; R^(6b) is H, methyl, ethyl,propyl, i-propyl or butyl; R^(6d) is methyl, phenyl, CF₃, and(CH₂)-phenyl; and r is 0 or
 1. 11. The compound of claim 10, wherein:ring B is selected from

 ring B being substituted with 0-1 R⁵; R¹ is selected from a C₆₋₁₀ arylgroup substituted with 0-3 R⁶ wherein the aryl group is selected fromphenyl, and a S-10 membered heteroaryl system containing 1-4 heteroatomsselected from N and O, substituted with 0-3 R⁶ wherein the heteroarylsystem is selected from indolyl and pyridinyl; R⁴ is selected from H,methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,allyl and (CH₂)_(r)C(O)R^(4b); R⁵ is selected from H, OH, OCH₃, andNR^(5a)R^(5a); R^(5a) is selected from H, methyl, ethyl, propyl,i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,propargyl, cyclopropyl, cyclopropylmethyl, acetyl, methylsulfonyl,—C(O)CF₃, C(═N)NH₂, benzyl, and —C(O)O-t-butyl; R⁶ is selected frommethyl, ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, CN,NR^(6a)R^(6a), C(O)H, C(O)OH, C(O)R^(6b), SR^(6d), S(O)_(p)R^(6d),S(O)₂NR^(6a)R^(6a), CF₃, and CH₂OH; R^(6b) is H, methyl, ethyl, propyl,i-propyl or butyl; R^(6d) is methyl; R⁷ is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F,CN, NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F, OCF₃, OCF₂CF₃, OCHF₂, andOCH₂F, C(O)OR^(7d), C(O)R^(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

R^(7a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl; R^(7b) is selected from cyclohexyl and CF₃;and R^(7d) is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, and t-butyl.
 12. The compound of claim 11, wherein: ring B isselected from

 ring B being substituted with 0-1 R⁵; R¹ is selected from a C₆₋₁₀ arylgroup substituted with 0-3 R⁶ wherein the aryl group is phenyl; R⁶ isselected from methyl, ethyl, propyl, i-propyl, F, Cl, Br, CN, SCH₃, andCF₃; R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, t-butyl, pentyl, hexyl, phenyl, adamantyl, benzyl, Cl,Br, I, F, CN, NO₂, NR^(7a)R^(7a), OR^(7d), NHC(O)NHR^(7a),NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F, OCF₃,OCF₂CF₃, OCHF₂, and OCH₂F, C(O)OR^(7d), C(O)R^(7b), andNR^(7f)C(O)NR^(7a)R^(7a); R^(7a) is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
 13. The compoundof claim 12, wherein E is selected from —CH₂—NH—, —C(O)—NH— and—SO₂—CH₂—.
 14. The compound of claim 1, wherein B is

 ring B being substituted with 0-1 R⁵; and R⁵ is selected from H,N(→O)R^(5a)R^(5a), N₃, NR^(5a)C(O)R^(5b), NR^(5a)C(O)H,NR^(5a)C(O)OR^(5d), NR^(5a)C(O)NR^(5a)R^(5a), and NR^(5a)R^(5a), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-2 heteroatomsselected from N, O, and S, substituted with 0-2 Me, wherein theheterocyclic system is selected from pyrrolidinyl, piperidinyl,pyrrolidin-2-one, and isothiazolidine 1,1-dioxide.
 15. The compound ofclaim 12, wherein Z is selected from a bond, —NR⁸C(O)—, —CO)NH—, and—NHC(O)NH—.
 16. The compound of claim 12, wherein R⁶ is selected frommethyl, ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, C(O)H,C(O)R^(6b), SR^(6d), S(O)_(p)R^(6d), CF₃, and CH₂OH; R^(6b) is H,methyl, ethyl, propyl, i-propyl or butyl; R^(6d) is methyl; R⁷ isselected from Cl, Br, NR^(7a)R^(7a), NR^(7a)C(O)OR^(7d), NHC(O)NHR^(7a),OCF₃, and CF₃; R^(7a) is selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl; R^(7d) is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl.
 17. The compoundof claim 1, wherein the compound is of formula (Ia) or (Ic)


18. The compound of claim 1, wherein the compound is of formula (I) isselected:2-{(3S)-1-[(1,2-cis)-2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester;2-{(3S)-1-[(1,2-cis)2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-amino;N-{(3S)-1-[(1S,2R,4R)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4S)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-cyclopropylmethyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-prop-2-ynyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)N-{(3S*)-[(1S*,2R*,4R*)-4-(Cyclopropylmethyl-isopropyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;1-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea;N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzenesulfonamide;N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-benzamide;{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea;N-[(3S)-1-((1S,2R,4R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidin-3-yl]-3-trifluoromethyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-4-(Allyl-isopropyl-amino)-2-benzenesulfonylmethyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide;1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrrolidine-3-carboxylicacid (3-trifluoromethyl-phenyl)-amide;(2-{(3S)-1-[(1S,2R)-2-(4-Methylsulfanyl-benzylamino)-cyclohexyl-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester;N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4(R)-(isopropyl-propyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;(±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;(±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;(±)1-[(1S*,2R*,4R*)-4-Isopropylmethylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;(±)1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one;(±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one;(±)1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-piperidin-2-one;(S)-3-(3-(trifluoromethyl)benzylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-(methylthio)phenylsulfonyl)methyl)cyclohexyl)pyrrolidin-2-one;3(R)-(3-(trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetate3(S)-(3-(Trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-onetrifluoroacetateN—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxoazepan-3-yl)-3-(trifluoromethyl)benzamide;N—((S)-1-((1S,2R,4R)-4-(dimethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopiperidin-3-yl)-3-(trifluoromethyl)benzamide;(R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one;(S*)-1-((1S*,2R*,4R*)-4-(isopropylmethyl)amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one;(S*)-3-(2-oxo-2-(3-(trifluoromethylphenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(R*)-3-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(R*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(S*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;((S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(−2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidin-2-one;((R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(−2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(isopropyl(ethyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(Diethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(naphthalen-1-ylamino)pyrrolidin-2-one;3-(Benzo[b]thiophen-3-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(S)-3-(6-chloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(S)-3-(6,8-dichloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;3,5-Dichloro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide;3-((E)-3(R*)-(trifluoromethyl)styryl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2-one;N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)benzamidede;N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamide;2-Amino-N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)-5-(trifluoromethoxy)benzamide;(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;3-(2-(Phenyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;3-(3,5-Bis(trifluoromethyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(2-(trifluoromethyl)phenylamino)pyrrolidin-2-one;1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(2-methoxyphenylamino)pyrrolidin-2-one;1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(3-(trifluoromethyl)phenylamino)pyrrolidin-2-one;1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(4-(trifluoromethyl)phenylamino)pyrrolidin-2-one;3-Chloro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;3-Fluoro-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethyl)benzamide;tert-Butyl(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate;N—((S)-2-Oxo-1-((1S,2R,4R)-4-(phenylamino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyridin-4-ylamino)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(thiazol-2-ylamino)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;Methyl(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate;N—((S)-1-((1S,2R,4R)-4-Formamido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;1-((1R,3R,4S)-4-((S)-2-Oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea;1-Methyl-3-((1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea;N—((S)-2-Oxo-1-((1S,2R,4R)-4-(2-oxopyrrolidin-1-yl)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N—((S)-1-((1S,2R,4R)-4-(1,1-dioxido-isothiazolidin-2-yl)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamide;3-Chloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamide;tert-Butyl2-(((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarbamate;2-Amino-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamide;N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide;N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;3,5-Dichloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;3-Chloro-N—((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamideN-Oxide;N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideN-Oxide;N—((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)benzamideN-Oxide;N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamideN-Oxide;N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-isopropylphenylsulfonyl)methyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(o-tolylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;N—((S)-1-((1S,2R,4R)-2-((4-Fluorophenylsulfonyl)methyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;3-Chloro-N-((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;2-Amino-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamidemide;1-[(1S,2R,4R)-(4-Amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluoromethylphenyl)]-5,6-dihydro-1H-pyridin-2-one;1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)]-5,6-dihydro-1H-pyridin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;1-[1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-dimethylamino-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-hydroxy-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-pyrrolidin-2-one;(3S)-3-(6-Adamantan-1-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrrolidin-2-one;3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;2-Phenyl-3H-imidazole-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;Preparation of1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6,7-dimethoxy-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-fluoro-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-isopropyl-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(2-tert-butyl-6-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one;1-[(1Sr2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-ethyl-quinazolin-4-ylamino)-pyrrolidin-2-one;N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1H-pyrrole-2-carboxamide;N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1-methyl-1H-pyrrole-2-carboxamide;1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-tert-butyl-pyrimido[5,4-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;2-tert-Butyl-pyrimidine-4-carboxylic acid{(3S*)-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;2-tert-Butyl-5-phenyl-pyrimidine-4-carboxylic acid{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;N-{(3S)-1-[1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-tert-butyl-benzamide;N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-bromo-5-tert-butyl-benzamide;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-trifluoromethoxy-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S)-3-(6-chloro-2-methylamino-quinazolin-4-ylamino)-pyrrolidin-2-one;(3S)-3-(6-Fluoro-quinazolin-4-ylamino)-1-[(1S2R,4R)-4-(isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-2-one;N-{1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-(3S)-3-yl}-2-chloro-5-trifluoromethyl-benzamide;(S)-3-(6-Bromoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(S)-3-(6,7-Difluoroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;(S)-3-(6-Methoxyquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(quinazolin-4-ylamino)pyrrolidin-2-one;3-Phenyl-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;(S)-3-(6-Iodoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;3-Tert-butyl-4-hydroxy-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;3-Amino-5-tert-butyl-N—((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)thiophene-2-carboxamide;N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-2-methyl-5-phenylfuran-3-carboxamide;N—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-nitrofuran-2-carboxamide;andN—((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-4-phenylthiophene-2-carboxamide.19. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 1. 20. A method for modulation of chemokine receptor activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 21. A method for modulationof MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that is mediated bythe CCR2 receptor comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim
 1. 22. Amethod for modulation of MCP-1 activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim
 1. 23. A method for treating disorders, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1, said disorders being selected fromosteoarthritis, aneurism, fever, cardiovascular effects, Crohn'sdisease, congestive heart failure, autoimmune diseases, HIV-infection,HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis,transplant arteriosclerosis, physically- or chemically-induced braintrauma, inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, rheumatoid arthritis, restinosis,organ transplantation, and cancer.
 24. The method for treatingdisorders, of claim 23, wherein said disorders being selected frompsoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis,physically- or chemically-induced brain trauma, inflammatory boweldisease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxicserum nephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, rheumatoid arthritis restinosis, organtransplantation, and cancer.
 25. The method for treating disorders, ofclaim 24, wherein said disorders being selected from alveolitis,colitis, systemic lupus erythematosus, nephrotoxic serum nephritis,glomerularnephritis, asthma, multiple sclerosis, artherosclerosis,rheumatoid arthritis restinosis, organ transplantation, and cancer. 26.The method for treating disorders, of claim 25, wherein said disordersbeing selected from asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis.
 27. A method for treating inflammatory diseases,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 28. A method for modulationof CCR2 activity comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 1. 29. Themethod for treating disorders, of claim 25, wherein said disorders beingselected from restinosis, organ transplantation, and cancer.
 30. Acompound of Formula (II)

wherein W is selected from H, I, and Br; Pg, at each occurrence, isindependently selected from an amine protecting group.
 31. The compoundof claim 30, wherein W is selected from H, I, and Br; and Pg, at eachoccurrence, is independently selected from benzyloxycarbonyl (Cbz) andtert-butyloxycarbonyl (Boc).
 32. A process for preparing a compound ofFormula (Ia)

or salt or stereoisomer thereof: wherein E is selected from—S(O)_(p)CHR^(e)—, —CHR^(e)NR^(e)—, —C(O)—NR^(e)—, —NR^(e)C(O)NR^(e)—,—SO₂—NR^(e)—, and NR^(e)SO₂NR^(e)—; R^(e) is independently selected fromH and C₁₋₃ alkyl; X is selected from O or S; Z is selected from a bond,—NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—, —NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—,—C(O)NR⁸—, —OC(O)NR⁸—, —NR⁸C(O)O—, —(CR¹⁵R¹⁵)_(l)—, —CR¹⁴═C—R⁴—,—CR¹⁵R¹⁵C(O)—, —C(O)CR¹⁵R¹⁵—, CR¹⁵R¹⁵C(═N—OR¹⁶)—, —O—CR¹⁴R¹⁴—,—CR¹⁴R¹⁴—O—, —O—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—,—S(O)_(p)—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—; whereinneither Z nor R¹³ are connected to a carbon atom labeled (b); bond (a)is a single or double bond; alternatively, when n is equal to 2, twoatoms labeled (b) may join through a double bond; R¹ is selected from aC₆₋₁₀ aryl group substituted with 0-5 R⁶ and a 5-10 membered heteroarylsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5R⁷ and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁷; R⁵, at eachoccurrence, is independently selected from H, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),(CRR)_(r)N(→O)R^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b),(CRR)_(r)OC(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)OR^(5d),(CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)H,(CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),(CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b),(CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), and a (CRR)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(5c); R^(5a), at each occurrence, isindependently selected from H, methyl substituted with 0-1 R^(5g), C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(5e), R^(5b), at each occurrence, isselected from C₁₋₆ alkyl substituted with 0-3 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(5e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),(CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)OC(O)NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)NR^(5f)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b),(CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b),(CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f),(CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from—C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), —CN, and (CH₂)_(r)phenyl;R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a),(CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(6b),(CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); alternatively, two R⁶ on adjacentatoms on R¹ may join to form a cyclic acetal; R^(6a), at eachoccurrence, is selected from H, methyl substituted with 0-1 R^(6g), C₂₋₆alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6b), at each occurrence, isselected from H, C₁₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(6e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(6e); R^(6d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(6e),C₃₋₈ alkynyl substituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(6e), C₂₋₄ haloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e); R^(6e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and(CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g) is independently selectedfrom —C(O)R^(6b), —C(O)OR^(6d), —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)C₃₋₁₀ carbocyclic residue and (CR′R′)_(r)phenyl substitutedwith 0-3 R^(7e); alternatively, two R⁷ on adjacent atoms on R² may jointo form a cyclic acetal; R^(7a), at each occurrence, is independentlyselected from H, methyl substituted with 0-1 R^(7g), C₂₋₆ alkylsubstituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e); R^(7b), at each occurrence, is selectedfrom C₁₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a(CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at eachoccurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(7e),C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃, C₂₋₄ haloalkyl,C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,C(O)OC₁₋₅ alkyl, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(7g) is independently selectedfrom —C(O)R^(7b), —C(O)OR^(7d), —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted withR^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with R^(6e); R⁸ is selected from H, C₁₋₄alkyl, and C₃₋₄ cycloalkyl; R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄cycloalkyl, —C(O)H, and —C(O)—C₁₋₄alkyl; R¹⁰ is independently selectedfrom H, and C₁₋₄alkyl substituted with 0-1 R^(10b), alternatively, twoR¹⁰ form ═O; R^(10b), at each occurrence, is independently selected from—OH, —SH, —NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄alkyl;alternatively, two R¹⁴s, along with the carbon atom to which they areattached, join to form a C₃₋₆ carbocyclic ring; R¹⁵, at each occurrence,is independently selected from H, C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl,NR^(15a)R^(15a), C(O)NR^(15a)R^(15a), NR^(15a)C(O)R^(15b),NR^(15a)C(O)OR^(15d), OC(O)NR^(15a)R^(15a), and (CHR)_(r)C(O)OR^(15d);alternatively, two R¹⁵s, along with the carbon atom or atoms to whichthey are attached, join to form a C₃₋₆ carbocyclic ring; R^(15a), ateach occurrence, is independently selected from H, and C₁₋₄ alkyl;R^(15b), at each occurrence, is independently selected from C₁₋₄ alkyl,C₃₋₆ alkenyl, and C₃₋₆ alkynyl; R^(15d), at each occurrence, isindependently selected from C₁₋₄ alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;R¹⁶ is selected from C₁₋₄ alkyl; l is selected from 1, 2 and 3; n isselected from 0, 1, 2, and 3; p, at each occurrence, is independentlyselected from 0, 1, and 2; q, at each occurrence, is independentlyselected from 1, 2, 3, and 4; r, at each occurrence, is independentlyselected from 0, 1, 2, 3, and 4; is selected from 0 and 1; and t, ateach occurrence, is independently selected from 2, 3, and 4; the stepscomprising reacting a compound of Formula IV,

with an electrophile and base to give a compound of Formula II;

wherein W is selected from H, I, and Br; Pg, at each occurrence, isindependently selected from an amine protecting group; reacting acompound of Formula II to give the compound of Formula (Ia).
 33. Aprocess for preparing a compound of Formula (II)

or salt or stereoisomer thereof, comprising reacting a compound ofFormula (IV)

with an electrophile and a baser wherein W is selected from I and Br;Pg, at each occurrence, is independently selected from an amineprotecting group.
 34. The process of claim 33 wherein the electrophileis selected from iodine, bromine, N-bromo-succimide, andN-iodosuccinimide; and the base is selected from n-butyl lithium,lithium diisopropylamide (LDA), sodium hydride, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)-amide, and Li—Al(O-tButyl)₄.
 35. A process forpreparing a compound of Formula (IIa)

or salt or stereoisomer thereof, comprising reduction of a compound ofFormula (II) with a reducing agent;

wherein W is selected from I and Br, and Pg, at each occurrence, isindependently selected from an amine protecting group.
 36. The processof claim 35, wherein the reducing agent is selected fromtris-(trimethylsilyl)silane, zinc metal, tributyltin hydride and AIBN.